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Zhong BY, Fan W, Guan JJ, Peng Z, Jia Z, Jin H, Jin ZC, Chen JJ, Zhu HD, Teng GJ. Combination locoregional and systemic therapies in hepatocellular carcinoma. Lancet Gastroenterol Hepatol 2025; 10:369-386. [PMID: 39993404 DOI: 10.1016/s2468-1253(24)00247-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Revised: 07/20/2024] [Accepted: 07/25/2024] [Indexed: 02/26/2025]
Abstract
Locoregional therapies play a fundamental role in the treatment of patients with early and intermediate and locally advanced hepatocellular carcinomas. With encouraging recent advances in immunotherapy-based systemic therapies, locoregional therapies are being both promoted and challenged by new systemic therapy options. Combined locoregional and systemic therapies might enhance treatment outcomes compared with either option alone. This Series paper summarises the existing data on locoregional and systemic therapies for hepatocellular carcinoma, and discusses evidence from studies investigating their combination with a focus on their synergistic efficacy and safety.
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Affiliation(s)
- Bin-Yan Zhong
- Center of Interventional Radiology and Vascular Surgery, Nurturing Center of Jiangsu Province for State Laboratory of AI Imaging & Interventional Radiology (Southeast University), Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, China; Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Wenzhe Fan
- Department of Interventional Oncology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Justin J Guan
- Division of Interventional Radiology, Department of Radiology, Cleveland Clinic, Cleveland, OH, USA
| | - Zhenwei Peng
- Department of Radiation Oncology, Cancer Center, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China; Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Zhongzhi Jia
- Department of Interventional and Vascular Surgery, The Affiliated Changzhou Second People's Hospital of Nanjing Medical University, Changzhou, China
| | - Haojie Jin
- Shanghai Cancer Institute, State Key Laboratory of Systems Medicine for Cancer, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhi-Cheng Jin
- Center of Interventional Radiology and Vascular Surgery, Nurturing Center of Jiangsu Province for State Laboratory of AI Imaging & Interventional Radiology (Southeast University), Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, China
| | - Jian-Jian Chen
- Center of Interventional Radiology and Vascular Surgery, Nurturing Center of Jiangsu Province for State Laboratory of AI Imaging & Interventional Radiology (Southeast University), Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, China
| | - Hai-Dong Zhu
- Center of Interventional Radiology and Vascular Surgery, Nurturing Center of Jiangsu Province for State Laboratory of AI Imaging & Interventional Radiology (Southeast University), Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, China
| | - Gao-Jun Teng
- Center of Interventional Radiology and Vascular Surgery, Nurturing Center of Jiangsu Province for State Laboratory of AI Imaging & Interventional Radiology (Southeast University), Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, China.
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2
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Yuan H, Zhang Y, Liu F, Wu Y, Huang X, Liu X, Jiang L, Xiao B, Zhu Y, Chen Q, Wu P, Jiang K. Exploring the biological mechanism and clinical value of perineural invasion in pancreatic cancer. Cancer Lett 2025; 613:217515. [PMID: 39892698 DOI: 10.1016/j.canlet.2025.217515] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 01/30/2025] [Accepted: 01/30/2025] [Indexed: 02/04/2025]
Abstract
Pancreatic cancer (PC) is an extremely aggressive malignancy, with a 5-year survival rate of only 13 %. Perineural invasion (PNI) is a hallmark pathological feature of PC and is observed in almost all cases. Accordingly, PC ranks highly among solid tumors in terms of PNI incidence. The interaction between PC and the nervous system plays a pivotal role in tumor growth and metastasis. In PC, PNI is a key driver of local tumor progression, distant metastasis, and poor prognosis. Clarification of tumor-nerve crosstalk and the underlying molecular mechanisms is needed to facilitate the development of new therapeutic strategies to slow PC progression and alleviate PNI-associated symptoms. In this review, we present a comprehensive overview of the manifestations and characteristics of PNI in PC, summarize the molecular networks that regulate PNI, examine the relationship between PNI and the tumor microenvironment, and discuss the current research challenges and future directions in this critical area.
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Affiliation(s)
- Hao Yuan
- Pancreas Centre, First Affiliated Hospital, Nanjing Medical University, Nanjing, China; Pancreas Institute, Nanjing Medical University, Nanjing, China
| | - Yufeng Zhang
- Pancreas Centre, First Affiliated Hospital, Nanjing Medical University, Nanjing, China; Pancreas Institute, Nanjing Medical University, Nanjing, China
| | - Fengyuan Liu
- Pancreas Centre, First Affiliated Hospital, Nanjing Medical University, Nanjing, China; Pancreas Institute, Nanjing Medical University, Nanjing, China
| | - Yang Wu
- Pancreas Centre, First Affiliated Hospital, Nanjing Medical University, Nanjing, China; Pancreas Institute, Nanjing Medical University, Nanjing, China
| | - Xumin Huang
- Pancreas Centre, First Affiliated Hospital, Nanjing Medical University, Nanjing, China; Pancreas Institute, Nanjing Medical University, Nanjing, China
| | - Xinjian Liu
- Department of Pathogen Biology, Nanjing Medical University, Nanjing, China
| | - Luyang Jiang
- Pancreas Centre, First Affiliated Hospital, Nanjing Medical University, Nanjing, China; Pancreas Institute, Nanjing Medical University, Nanjing, China
| | - Bin Xiao
- Pancreas Centre, First Affiliated Hospital, Nanjing Medical University, Nanjing, China; Pancreas Institute, Nanjing Medical University, Nanjing, China
| | - Yi Zhu
- Pancreas Centre, First Affiliated Hospital, Nanjing Medical University, Nanjing, China; Pancreas Institute, Nanjing Medical University, Nanjing, China; Department of General Surgery, First Affiliated Hospital, Nanjing Medical University, Nanjing, China.
| | - Qun Chen
- Pancreas Centre, First Affiliated Hospital, Nanjing Medical University, Nanjing, China; Pancreas Institute, Nanjing Medical University, Nanjing, China.
| | - Pengfei Wu
- Pancreas Centre, First Affiliated Hospital, Nanjing Medical University, Nanjing, China; Pancreas Institute, Nanjing Medical University, Nanjing, China.
| | - Kuirong Jiang
- Pancreas Centre, First Affiliated Hospital, Nanjing Medical University, Nanjing, China; Pancreas Institute, Nanjing Medical University, Nanjing, China.
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Cereda V, D’Andrea MR. Pancreatic cancer: failures and hopes-a review of new promising treatment approaches. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2025; 6:1002299. [PMID: 40124650 PMCID: PMC11926728 DOI: 10.37349/etat.2025.1002299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Accepted: 02/22/2025] [Indexed: 03/25/2025] Open
Abstract
Pancreatic cancer is a challenging disease with limited treatment options and a high mortality rate. Just few therapy advances have been made in recent years. Tumor microenvironment, immunosuppressive features and mutational status represent important obstacles in the improvement of survival outcomes. Up to now, first-line therapy did achieve a median overall survival of less than 12 months and this discouraging data lead clinicians all over the world to focus their efforts on various fields of investigation: 1) sequential cycling of different systemic therapy in order to overcome mechanisms of resistance; 2) discovery of new predictive bio-markers, in order to target specific patient population; 3) combination treatment, in order to modulate the tumor microenvironment of pancreatic cancer; 4) new modalities of the delivery of drugs in order to pass the physical barrier of desmoplasia and tumor stroma. This review shows future directions of treatment strategies in advanced pancreatic cancer through a deep analysis of these recent macro areas of research.
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Affiliation(s)
- Vittore Cereda
- Asl Roma 4, Hospital S. Paolo Civitavecchia, 00053 Civitavecchia, Italy
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Jagtap N, Kumar CS, Lakhtakia S, Ramchandani M, Memon SF, Asif S, Kalapala R, Nabi Z, Basha J, Gupta R, Tandan M, Reddy DN. Adjuvant endobiliary radio-frequency ablation combined with self-expandable biliary metal stents for unresectable malignant hilar strictures: A pragmatic comparative study. Indian J Gastroenterol 2025; 44:72-79. [PMID: 39240508 DOI: 10.1007/s12664-024-01668-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Accepted: 07/31/2024] [Indexed: 09/07/2024]
Abstract
INTRODUCTION The role of endo-biliary radio-frequency ablation (EB-RFA) in treating malignant biliary strictures remains a subject of controversy. This study aims to assess the efficacy and safety of EB-RFA in conjunction with self-expandable metal stents (SEMS) compared to SEMS alone. METHODS This single-center prospective pragmatic comparative study, conducted between June 2021 and November 2022, involved 23 patients undergoing EB-RFA plus SEMS and 48 patients undergoing SEMS for unresectable malignant hilar obstruction. The study evaluated overall survival, stent patency and adverse events. RESULTS Seventy-one patients (mean age [SD], 57.8 [11.2] years; 73.2% men) were enrolled. The clinical success rates did not significantly differ between the two groups (78.3% in EB-RFA and 66.6% in SEMS; p 0.316). The median (95% CI) overall survival was 155 (79.87-230.13) days in the EB-RFA group, contrasting with 86.0 (78.06-123.94) days in the SEMS group (p 0.020). The presence of carcinoma gallbladder (p 0.035; HR 0.55; 95% CI 0.32-0.96) and EB-RFA (p 0.047; HR 1.88; 95% CI 1.01-3.49) independently predicted overall survival. Median (95% CI) stent patency was 143.0 (95% CI, 61.61-224.39) days in the EB-RFA group compared to 78.0 (95% CI, 32.74-123.26) days in the SEMS group (p 0.019). The presence of carcinoma gallbladder (p 0.046, HR 0.60; 95% CI, 0.36-0.99), EB-RFA (p 0.023; HR 1.92; 95% CI, 1.10-3.36) and chemotherapy (p 0.017, HR 1.91; 95% CI, 1.12-3.26) independently predicted longer stent patency. There was no difference in procedure-related adverse events in both groups. CONCLUSION EB-RFA with SEMS placement proves to be a safe and effective technique for palliative biliary decompression in patients with malignant biliary strictures, demonstrating superior overall survival and stent patency compared to SEMS alone. Further confirmation through multi-center trials is warranted. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov (ID: NCT05320328).
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Affiliation(s)
- Nitin Jagtap
- Department of Medical Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, 500 082, India.
| | - C Sai Kumar
- Department of Medical Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, 500 082, India
| | - Sundeep Lakhtakia
- Department of Medical Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, 500 082, India
| | - Mohan Ramchandani
- Department of Medical Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, 500 082, India
| | - Sana Fathima Memon
- Department of Medical Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, 500 082, India
| | - Shujaath Asif
- Department of Medical Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, 500 082, India
| | - Rakesh Kalapala
- Department of Medical Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, 500 082, India
| | - Zaheer Nabi
- Department of Medical Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, 500 082, India
| | - Jahangeer Basha
- Department of Medical Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, 500 082, India
| | - Rajesh Gupta
- Department of Medical Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, 500 082, India
| | - Manu Tandan
- Department of Medical Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, 500 082, India
| | - D Nageshwar Reddy
- Department of Medical Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, 500 082, India
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Kudaravalli P, Singh S, Vinayek R, Aswath G, Crinò SF, Machicado J, Facciorusso A. Reducing the incidence of pancreatic cancer through radiofrequency ablation of mucinous cystic neoplasms: What is the evidence? Best Pract Res Clin Gastroenterol 2025; 74:101986. [PMID: 40210331 DOI: 10.1016/j.bpg.2025.101986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2024] [Revised: 01/08/2025] [Accepted: 01/24/2025] [Indexed: 03/04/2025]
Abstract
Pancreatic cystic lesions are mostly discovered incidentally during cross-sectional imaging for other indications. They range from benign cysts to premalignant lesions, posing a risk for development of pancreatic cancer. Surveillance of cysts with low-risk features and surgical resection of high-risk ones has been the standard of care. However, the lack of consensus between national society guidelines results in discordant management and follow-up. One of the upcoming therapeutic modalities for pancreatic cysts, including mucinous cystic neoplasms (MCN), is endoscopic ultrasound (EUS)-guided interventions, including injection of chemotherapeutic agents or EUS-guided radiofrequency ablation (EUS-RFA). EUS-RFA is emerging as a promising minimally invasive tool with the need for further investigation to understand its clinical utility. This review discusses the physiology, clinical studies, adverse events, and future perspectives of RFA for various pancreatic lesions, with particular regard with MCN.
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Affiliation(s)
- Pujitha Kudaravalli
- Gastroenterology & Hepatology, Lahey Hospital & Medical Center, Burlington, MA, United States.
| | - Sahib Singh
- Department of Internal Medicine, Sinai Hospital of Baltimore, Baltimore, MD, 21215, United States.
| | - Rakesh Vinayek
- Gastroenterology & Hepatology, Sinai Hospital of Baltimore, Baltimore, MD, 21215, United States.
| | - Ganesh Aswath
- Gastroenterology & Hepatology, State University of New York Upstate Medical University, Syracuse, NY, United States.
| | - Stefano Francesco Crinò
- Diagnostic and Interventional Endoscopy of Pancreas, The Pancreas Institute, University of Verona, 37134, Verona, Italy.
| | - Jorge Machicado
- Division of Gastroenterology, Michigan Medicine, University of Michigan, Ann Arbor, MI, United States.
| | - Antonio Facciorusso
- Gastroenterology Unit, Department of Experimental Medicine, Università del Salento, 73100, Lecce, Italy.
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Musiu C, Adamo A, Caligola S, Agostini A, Frusteri C, Lupo F, Boschi F, Busato A, Poffe O, Anselmi C, Vella A, Wang T, Dusi S, Piro G, Carbone C, Tortora G, Marzola P, D'Onofrio M, Crinò SF, Corbo V, Scarpa A, Salvia R, Malleo G, Lionetto G, Sartoris S, Ugel S, Bassi C, Bronte V, Paiella S, De Sanctis F. Local ablation disrupts immune evasion in pancreatic cancer. Cancer Lett 2025; 609:217327. [PMID: 39580047 DOI: 10.1016/j.canlet.2024.217327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 11/04/2024] [Accepted: 11/12/2024] [Indexed: 11/25/2024]
Abstract
BACKGROUND Pancreatic cancer (PC) is characterised by late diagnosis, tumour heterogeneity, and a peculiar immunosuppressive microenvironment, leading to poor clinical outcomes. Local ablative techniques have been proposed to treat unresectable PC patients, although their impact on activating the host immune system and overcoming resistance to immunotherapy remains elusive. METHODS We dissected the immune-modulatory abilities triggered by local ablation in mouse and human PC models and human specimens, integrating phenotypic and molecular technologies with functional assays. RESULTS Local ablation treatment performed in mice bearing orthotopic syngeneic PC tumours triggered tumour necrosis and a short-term inflammatory process characterised by the prompt increase of HMGB1 plasma levels, coupled with an enhanced amount of circulating and tumour infiltrating myeloid cells and increased MHCII expression in splenic myeloid antigen-presenting cells. Local ablation synergised with immunotherapy to restrict tumour progression and improved the survival of PC-bearing mice by evoking a T lymphocyte-dependent anti-tumour immune response. By integrating spatial transcriptomics with histological techniques, we pinpointed how combination therapy could reshape TME towards an anti-tumour milieu characterised by the preferential entrance and colocalization of activated T lymphocytes and myeloid cells endowed with antigen presentation features instead of T regulatory lymphocytes and CD206-expressing tumour-associated macrophages. In addition, treatment-dependent TME repolarization extended to neoplastic cells, promoting a shift from squamous to a more differentiated classical phenotype. Finally, we validated the immune regulatory properties induced by local ablation in PC patients and identified an association of the short-term treatment-dependent increase of neutrophils, NLR and HMGB1 with a longer time to progression. CONCLUSION Therefore, local ablation might overcome the current limitations of immunotherapy in PC.
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Affiliation(s)
- Chiara Musiu
- Department of Medicine, Section of Immunology, University of Verona Hospital Trust, Verona, Italy
| | - Annalisa Adamo
- Department of Medicine, Section of Immunology, University of Verona Hospital Trust, Verona, Italy
| | | | - Antonio Agostini
- Medical Oncology, Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Cristina Frusteri
- Department of Medicine, Section of Immunology, University of Verona Hospital Trust, Verona, Italy
| | - Francesca Lupo
- Department of Engineering for Innovative Medicine University of Verona Hospital Trust, Verona, Italy
| | - Federico Boschi
- Department of Engineering for Innovative Medicine University of Verona Hospital Trust, Verona, Italy
| | - Alice Busato
- Assessment Department Aptuit S.r.l., an Evotec Company, Verona, Italy
| | - Ornella Poffe
- Department of Medicine, Section of Immunology, University of Verona Hospital Trust, Verona, Italy
| | - Cristina Anselmi
- Department of Medicine, Section of Immunology, University of Verona Hospital Trust, Verona, Italy
| | - Antonio Vella
- Department of Medicine, Section of Immunology, University of Verona Hospital Trust, Verona, Italy
| | - Tian Wang
- Department of Medicine, Section of Immunology, University of Verona Hospital Trust, Verona, Italy
| | - Silvia Dusi
- Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Geny Piro
- Medical Oncology, Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Carmine Carbone
- Medical Oncology, Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Giampaolo Tortora
- Medical Oncology, Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Department of Translational Medicine, Catholic University of the Sacred Heart, Rome, Italy
| | - Pasquina Marzola
- Department of Engineering for Innovative Medicine University of Verona Hospital Trust, Verona, Italy
| | - Mirko D'Onofrio
- Department of Diagnostics and Public Health, Radiology Section, University of Verona Hospital Trust, Verona, Italy
| | - Stefano Francesco Crinò
- Department of Surgery, Dentistry, Paediatrics and Gynaecology, Gastroenterology and Digestive Endoscopy Unit, Pancreas Institute, University of Verona Hospital Trust, Verona, Italy
| | - Vincenzo Corbo
- Department of Engineering for Innovative Medicine University of Verona Hospital Trust, Verona, Italy
| | - Aldo Scarpa
- Department of Diagnostics and Public Health, Pathological Anatomy Section, University of Verona Hospital Trust, Verona, Italy
| | - Roberto Salvia
- Department of Surgery, Dentistry, Paediatrics and Gynaecology, General and Pancreatic Surgery Unit, Pancreas Institute, University of Verona Hospital Trust, Verona, Italy
| | - Giuseppe Malleo
- Department of Surgery, Dentistry, Paediatrics and Gynaecology, General and Pancreatic Surgery Unit, Pancreas Institute, University of Verona Hospital Trust, Verona, Italy
| | - Gabriella Lionetto
- Department of Surgery, Dentistry, Paediatrics and Gynaecology, General and Pancreatic Surgery Unit, Pancreas Institute, University of Verona Hospital Trust, Verona, Italy
| | - Silvia Sartoris
- Department of Medicine, Section of Immunology, University of Verona Hospital Trust, Verona, Italy
| | - Stefano Ugel
- Department of Medicine, Section of Immunology, University of Verona Hospital Trust, Verona, Italy.
| | - Claudio Bassi
- Department of Engineering for Innovative Medicine University of Verona Hospital Trust, Verona, Italy
| | | | - Salvatore Paiella
- Department of Surgery, Dentistry, Paediatrics and Gynaecology, General and Pancreatic Surgery Unit, Pancreas Institute, University of Verona Hospital Trust, Verona, Italy
| | - Francesco De Sanctis
- Department of Medicine, Section of Immunology, University of Verona Hospital Trust, Verona, Italy.
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Matsumoto K, Kato H, Tsutsumi K, Otsuka M. Current status of endoscopic ultrasound-guided antitumor treatment for pancreatic cancer. Dig Endosc 2025; 37:18-28. [PMID: 38752622 PMCID: PMC11718125 DOI: 10.1111/den.14815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Accepted: 04/15/2024] [Indexed: 01/11/2025]
Abstract
Endoscopic ultrasound (EUS) was developed in the 1990s and has significantly transformed pancreatic tumor diagnosis. Subsequently, EUS has rapidly shifted from being a purely diagnostic procedure to being used in a wide range of interventional procedures. Recently, new therapeutic techniques, such as EUS-guided fine needle injection (EUS-FNI) or radiofrequency ablation (RFA), have been developed to deliver various antitumor agents. Despite technological advancements, pancreatic cancer (PC) has a poor prognosis and improvements in treatment outcomes are urgently required. One of the reasons for the limited response to antitumor agents in PC is the abundant desmoplasia and hypovascular nature of the tumor, complicating drug delivery into the tumor. Thus, changing the tumor microenvironment may be important to enhance the effectiveness of chemotherapy, and direct injection of antitumor agents into the tumor under EUS guidance can help overcome treatment challenges in PC. Treatment approaches using the EUS-FNI or RFA technique are expected to further improve the prognosis of PC. Therefore, this study reviewed the existing literature on EUS-guided antitumor therapy, specifically highlighting its application in PC to address the current challenges and to identify potential advancements in the field.
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Affiliation(s)
- Kazuyuki Matsumoto
- Department of Gastroenterology and HepatologyOkayama University HospitalOkayamaJapan
| | - Hironari Kato
- Department of Gastroenterology and HepatologyOkayama University HospitalOkayamaJapan
| | - Koichiro Tsutsumi
- Department of Gastroenterology and HepatologyOkayama University HospitalOkayamaJapan
| | - Motoyuki Otsuka
- Department of Gastroenterology and HepatologyOkayama University HospitalOkayamaJapan
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Birrer M, Saad B, Drews S, Pradella C, Flaifel M, Charitakis E, Ortlieb N, Haberstroh A, Ochs V, Taha-Mehlitz S, Burri E, Heigl A, Frey DM, Cattin PC, Honaker MD, Taha A, Rosenberg R. Radiofrequency ablation (RFA) in unresectable pancreatic adenocarcinoma: meta-analysis & systematic review. Surg Endosc 2025; 39:141-152. [PMID: 39658672 PMCID: PMC11666652 DOI: 10.1007/s00464-024-11450-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Accepted: 11/23/2024] [Indexed: 12/12/2024]
Abstract
BACKGROUND Pancreatic adenocarcinoma remains a challenging malignancy with a poor prognosis. Radiofrequency ablation (RFA) has emerged as a potential treatment for unresectable pancreatic adenocarcinoma (UPAC) aimed at improving survival and quality of life. This meta-analysis and systematic review evaluates the outcomes of RFA in UPAC. METHODS A comprehensive search was conducted in MEDLINE, Embase, Scopus, and Cochrane Central databases from inception to October 2023. Studies included patients over 18 years with UAPC undergoing RFA. Survival rates and complication rates were assessed as primary outcomes. Data were pooled using random-effects models, and heterogeneity was assessed with I2 statistics. ROBINS-I tool was used for quality assessment. RESULTS Nine studies encompassing 265 patients met the inclusion criteria. The mean age was 64.5 years, with 42.5% female participants. Survival analysis showed that at 30 days post-RFA, the mortality rate was 3.3%. At 6 months, the mortality rate was 20.9%, increasing to 50.4% at 12 months. At 24 months, the mortality rate was 61.9%. The pooled mean survival period at 12 and 24 months was 9.18 months and 14.26 months, respectively. Overall, 78.4% of patients died during the follow-up period, with an overall mean survival period of 12.27 months. The most common were intra-abdominal (10.1%), pancreatic (9.8%), and hepatobiliary (6.7%) complications. CONCLUSIONS RFA shows potential in the management of unresectable pancreatic adenocarcinoma, with a manageable safety profile. However, the high heterogeneity and risk of bias in available studies highlight the need for well-designed randomized controlled trials to confirm these findings and establish standardized protocols.
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Affiliation(s)
- Mathias Birrer
- Department of Visceral Surgery, Cantonal Hospital Baselland, Liestal, Switzerland
- Faculty of Medicine, University of Basel, Basel, Switzerland
| | - Baraa Saad
- School of Medicine, St George's University of London, London, UK
| | - Susanne Drews
- Department of Visceral Surgery, Cantonal Hospital Baselland, Liestal, Switzerland
| | - Charlotte Pradella
- Department of Visceral Surgery, Cantonal Hospital Baselland, Liestal, Switzerland
| | - Mariana Flaifel
- School of Medicine, St George's University of London, London, UK
| | | | | | - Amanda Haberstroh
- Laupus Health Sciences Library, East Carolina University, Greenville, NC, USA
| | - Vincent Ochs
- Department of Biomedical Engineering, Faculty of Medicine, University of Basel, Allschwil, Switzerland
| | - Stephanie Taha-Mehlitz
- Clarunis, Department of Visceral Surgery, University Center for Gastrointestinal and Liver Diseases, St. Clara Hospital and University Hospital Basel, Basel, Switzerland
| | - Emanuel Burri
- Department of Gastroenterology and Hepatology, Medical University Clinic, Cantonal Hospital Baselland, Liestal, Switzerland
| | - Andres Heigl
- Department of Visceral Surgery, Cantonal Hospital Baselland, Liestal, Switzerland
| | - Daniel M Frey
- Faculty of Medicine, University of Basel, Basel, Switzerland
- Department of Surgery, Klinik-Impuls, Zurich, Switzerland
| | - Philippe C Cattin
- Department of Biomedical Engineering, Faculty of Medicine, University of Basel, Allschwil, Switzerland
| | - Michael D Honaker
- Department of Surgery, Brody School of Medicine, East Carolina University, Greenville, NC, USA
| | - Anas Taha
- Department of Visceral Surgery, Cantonal Hospital Baselland, Liestal, Switzerland.
- Department of Biomedical Engineering, Faculty of Medicine, University of Basel, Allschwil, Switzerland.
- Department of Surgery, Brody School of Medicine, East Carolina University, Greenville, NC, USA.
| | - Robert Rosenberg
- Department of Visceral Surgery, Cantonal Hospital Baselland, Liestal, Switzerland
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Lorenzo D, Aguilera Munoz L, Vedie AL, Prat F, Dokmak S, Sauvanet A, Maire F, de Mestier L, Copin P, Dioguardi Burgio M, Couvelard A, Haumaitre C, Cros J, Rebours V. Mural nodules and prevalence of high-grade dysplasia in branch duct intraductal papillary mucinous neoplasm of the pancreas undergoing resection. Br J Surg 2024; 111:znae292. [PMID: 39612583 DOI: 10.1093/bjs/znae292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 09/23/2024] [Accepted: 10/25/2024] [Indexed: 12/01/2024]
Abstract
BACKGROUND A mural module (MN) within a branch-duct intraductal papillary mucinous neoplasm (BD-IPMN) could be a potential target for local treatment. The main aim was to describe the location of the highest grade of dysplasia relative to the mural module to assess the relevance of local treatment. METHODS Observational study of patients who underwent a pancreatic resection for suspected high-risk IPMN because of a mural module within a BD-IPMN (2012-2022). All patients had preoperative imaging confirming the enhancing mural module. The mural module was considered as a theoretical appropriate target for local destruction if no cancer or high-grade dysplasia (HGD) was described elsewhere than in the mural module. RESULTS Eighty-two patients (male: 44 (54%); mean age: 65 ± 9.2 years) were included. The mean size of BD-IPMN containing the mural module was 32 ± 14.8 mm. The mural module mean diameter was 10.5 ± 5.6 mm, and the main pancreatic duct (MPD) mean diameter was 5.2 ± 3.6 mm. Six patients presented invasive carcinoma (7%), 37 had HGD (45%), and 39 (48%) had exclusively low-grade dysplasia. The mural module was dysplastic in 70 cases (85%). The mural module was considered a relevant target for local ablation in 45 patients (55%), whereas 37 patients (45%) had HGD/invasive carcinoma distant from the mural module. HGD was exclusively present in the mural module in 6/82 patients (7%). Factors independently associated with 'relevant indication for local treatment' were female gender (P = 0.004; OR = 5.2, 95% c.i. 1.7 to 15.9) and MPD < 5 mm (P < 0.0001; OR = 8.6, 95% c.i. 2.7 to 26.8). CONCLUSION In resected pancreata, BD-IPMN mural modules are associated with HGD distant from the mural module almost half of cases. The findings question the safety of local treatment, supporting pancreatectomy as the best approach.
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Affiliation(s)
- Diane Lorenzo
- Department of Digestive Endoscopy, Université Paris Cité, Beaujon University Hospital (APHP), Clichy, France
- Centre of Research on Inflammation (CRI), INSERM U1149, Paris, France
| | - Lina Aguilera Munoz
- Centre of Research on Inflammation (CRI), INSERM U1149, Paris, France
- Department of Pancreatology and Digestive Oncology, Université Paris Cité, Beaujon University Hospital (APHP), CRMR PaRaDis Pancreatic Rare Diseases, Clichy, France
| | - Anne-Laure Vedie
- Department of Pancreatology and Digestive Oncology, Université Paris Cité, Beaujon University Hospital (APHP), CRMR PaRaDis Pancreatic Rare Diseases, Clichy, France
| | - Frédéric Prat
- Department of Digestive Endoscopy, Université Paris Cité, Beaujon University Hospital (APHP), Clichy, France
- Centre of Research on Inflammation (CRI), INSERM U1149, Paris, France
| | - Safi Dokmak
- Department of Hepatobiliary and Pancreatic Surgery, Université Paris Cité, Beaujon University Hospital (APHP), Clichy, France
| | - Alain Sauvanet
- Department of Hepatobiliary and Pancreatic Surgery, Université Paris Cité, Beaujon University Hospital (APHP), Clichy, France
| | - Frédérique Maire
- Department of Pancreatology and Digestive Oncology, Université Paris Cité, Beaujon University Hospital (APHP), CRMR PaRaDis Pancreatic Rare Diseases, Clichy, France
| | - Louis de Mestier
- Centre of Research on Inflammation (CRI), INSERM U1149, Paris, France
- Department of Pancreatology and Digestive Oncology, Université Paris Cité, Beaujon University Hospital (APHP), CRMR PaRaDis Pancreatic Rare Diseases, Clichy, France
| | - Pauline Copin
- Department of Radiology, Hôpital Beaujon, AP-HP.Nord, Clichy, France
| | - Marco Dioguardi Burgio
- Centre of Research on Inflammation (CRI), INSERM U1149, Paris, France
- Department of Radiology, Hôpital Beaujon, AP-HP.Nord, Clichy, France
| | - Anne Couvelard
- Centre of Research on Inflammation (CRI), INSERM U1149, Paris, France
- Department of Pathology, Université Paris Cité, Bichat University Hospital (APHP), Paris, France
| | - Cécile Haumaitre
- Centre of Research on Inflammation (CRI), INSERM U1149, Paris, France
| | - Jérôme Cros
- Centre of Research on Inflammation (CRI), INSERM U1149, Paris, France
- Department of Pathology, Université Paris Cité, FHU MOSAIC, Beaujon University Hospital (APHP), Clichy, France
| | - Vinciane Rebours
- Centre of Research on Inflammation (CRI), INSERM U1149, Paris, France
- Department of Pancreatology and Digestive Oncology, Université Paris Cité, Beaujon University Hospital (APHP), CRMR PaRaDis Pancreatic Rare Diseases, Clichy, France
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10
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Chavan R, Thosani N, Kothari S. Role of Endoscopic Ultrasound-Guided Radiofrequency Ablation in Pancreatic Lesions: Where Are We Now and What Does the Future Hold? Cancers (Basel) 2024; 16:3662. [PMID: 39518100 PMCID: PMC11544980 DOI: 10.3390/cancers16213662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2024] [Revised: 10/17/2024] [Accepted: 10/19/2024] [Indexed: 11/16/2024] Open
Abstract
Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) has emerged as an effective and minimally invasive treatment for pancreatic lesions, particularly in patients at high surgical risk. Utilizing thermal energy, RFA induces the coagulative necrosis of the tissue and potentially triggers immunomodulation by releasing intracellular antigens. Numerous studies have confirmed the technical feasibility, safety, and efficacy of EUS-RFA in pancreatic neuroendocrine tumors and premalignant cystic lesions, with an acceptable profile of adverse events. The technique's potential immunomodulatory effects offer intriguing implications for the treatment of advanced pancreatic malignancies, encouraging further evaluation. This review paper aims to highlight the EUS-RFA principles, technology, and clinical applications in various pancreatic lesions and safety, and the future research directions.
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Affiliation(s)
| | - Nirav Thosani
- The University of Texas Health Science Center, 7000 Fannin, Suite 1706, Houston, TX 77030, USA;
| | - Shivangi Kothari
- University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA
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11
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Flak RV, Kofod-Olsen E, Sølvsten ND, Naujokaite G, Agger R, Stender MT, Christensen S, Shim S, Poulsen LØ, Detlefsen S, Thorlasius-Ussing O, Ladekarl M. Pembrolizumab followed by irreversible electroporation of a liver metastasis in pancreatic cancer patients. iScience 2024; 27:111026. [PMID: 39610376 PMCID: PMC11602522 DOI: 10.1016/j.isci.2024.111026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 05/29/2024] [Accepted: 09/20/2024] [Indexed: 11/30/2024] Open
Abstract
Preclinical studies suggest that irreversible electroporation (IRE) increases the effect of immune checkpoint inhibition in pancreatic cancer (PC). Patients with PC received PD-1 inhibitor pembrolizumab and, on day 10, percutaneous IRE of a liver metastasis. Blood samples were analyzed for immune cell subsets and inflammation related proteins. mRNA expression profiling was done in sequential biopsies. Treatment was safe, but the trial was terminated early. The response rate in eight patients was 0% and tumor growth was exponential. A drop in circulating plasmacytoid dendritic cells and a rise in several cytokines and proteins, especially PD-1, after immunotherapy was observed. In liver metastases, immune stimulatory genes were upregulated and immune suppressive genes were downregulated after pembrolizumab, while markers of effector T cells were unchanged. Treatment was safe but showed no efficacy in PC. Immunotherapy induced an immune permissive tumor microenvironment but with no increase in effector cells.
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Affiliation(s)
- Rasmus Virenfeldt Flak
- Department of Gastrointestinal Surgery and Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark
| | - Emil Kofod-Olsen
- Department of Health Science and Technology, Aalborg University, Aalborg, Denmark
| | - Nikolaj Dich Sølvsten
- Department of Gastrointestinal Surgery and Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark
| | | | - Ralf Agger
- Department of Health Science and Technology, Aalborg University, Aalborg, Denmark
| | - Mogens Tornby Stender
- Department of Gastrointestinal Surgery and Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Signe Christensen
- Department of Oncology and Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark
| | - Susy Shim
- Department of Oncology and Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark
| | - Laurids Østergaard Poulsen
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
- Department of Oncology and Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark
| | - Sönke Detlefsen
- Department of Pathology, Odense Pancreas Center (OPAC), Odense University Hospital, Odense, Denmark
- Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
| | - Ole Thorlasius-Ussing
- Department of Gastrointestinal Surgery and Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Morten Ladekarl
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
- Department of Oncology and Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark
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12
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Rimbaș M, Dumitru AC, Tripodi G, Larghi A. EUS-Guided Radiofrequency Ablation Therapy for Pancreatic Neoplasia. Diagnostics (Basel) 2024; 14:2111. [PMID: 39410514 PMCID: PMC11476430 DOI: 10.3390/diagnostics14192111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2024] [Revised: 09/18/2024] [Accepted: 09/20/2024] [Indexed: 10/20/2024] Open
Abstract
Radiofrequency ablation (RFA) under endoscopic ultrasound (EUS) guidance has been developed and utilized over the last decade to provide the loco-regional treatment of solid and cystic pancreatic neoplastic lesions. The advantage of this approach relies on the close proximity of the EUS transducer to the target pancreatic lesion, which, coupled with the development of specifically designed RFA ablation devices, has made the procedure minimally invasive, with a clear reduction in adverse events as compared to the high morbidity of the surgical approach. EUS-RFA has been applied so far to pancreatic functional and non-functional neuroendocrine neoplasms, pancreatic ductal adenocarcinoma or metastases to the pancreas, and pancreatic neoplastic cysts. Excluding neuroendocrine tumors, for other indications, most of these procedures have been performed in patients who refused surgery or were at high surgical risk. More studies evaluating EUS-RFA in selected patients, not at surgical risk, are gradually becoming available and will pave the road to extend the indications for this therapeutic approach, also in association with other oncological therapies. The present manuscript will critically review the available evidence in the field of the EUS-guided RFA of solid and cystic pancreatic neoplasms.
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Affiliation(s)
- Mihai Rimbaș
- Gastroenterology Department, Colentina Clinical Hospital, Carol Davila University of Medicine, 020125 Bucharest, Romania; (M.R.); (A.-C.D.)
| | - Andra-Cristiana Dumitru
- Gastroenterology Department, Colentina Clinical Hospital, Carol Davila University of Medicine, 020125 Bucharest, Romania; (M.R.); (A.-C.D.)
| | - Giulia Tripodi
- Digestive Endoscopy Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy;
- CERTT, Center for Endoscopic Research Therapeutics and Training, Catholic University, 00168 Rome, Italy
| | - Alberto Larghi
- Digestive Endoscopy Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy;
- CERTT, Center for Endoscopic Research Therapeutics and Training, Catholic University, 00168 Rome, Italy
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13
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Shin IS, Moon JH, Lee YN, Myeong JH, Lee TH, Yang JK, Cho YD, Park SH. Impact of temperature-controlled endobiliary radiofrequency ablation for inoperable hilar cholangiocarcinoma: A propensity score-matched analysis. Endosc Int Open 2024; 12:E535-E544. [PMID: 38720905 PMCID: PMC11077275 DOI: 10.1055/a-2276-1897] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Accepted: 02/20/2024] [Indexed: 05/12/2024] Open
Abstract
Background and study aims Endobiliary radiofrequency ablation (RFA) can be an effective palliative treatment, but few studies have evaluated its outcomes for malignant obstruction in the hilar bile duct, which has a thin wall and complex duct-vascular contacts. We evaluated the efficacy and safety of temperature-controlled endobiliary RFA, which can reduce the risk of unintentional thermal injury by maintaining the temperature of the ablation segment, in the treatment of inoperable hilar cholangiocarcinoma (CCA). Patients and methods After propensity score matching, 64 patients with inoperable hilar CCA were categorized to the RFA + stent group (endobiliary RFA with stenting; n=32) or stent-only group (stenting only; n=32). The evaluated outcomes were the median time to recurrent biliary obstruction (RBO), overall survival (OS), and adverse events (AEs). Results Technical success was achieved in all patients. The clinical success rate was 93.8% in the RFA + stent group and 87.5% in the stent-only group ( P =0.672). The median time to RBO was 242 days in the RFA + stent group and 168 days in the stent-only group ( P =0.031). The median OS showed a non-significant tendency to be higher in the RFA + stent group (337 versus 296 days; P =0.260). Overall AE rates were comparable between the two groups (12.5% vs 9.4%, P =1.000). Conclusions Temperature-controlled endobiliary RFA resulted in favorable stent patency without increasing the rate of AEs but it did not significantly increase OS in patients with inoperable hilar CCA (Clinical trial registration number: KCT0008576).
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Affiliation(s)
- Il Sang Shin
- Digestive Disease Center and Research Institute, Department of Internal Medicine, SoonChunHyang University School of Medicine, Bucheon, Korea
| | - Jong Ho Moon
- Digestive Disease Center and Research Institute, Department of Internal Medicine, SoonChunHyang University School of Medicine, Bucheon, Korea
| | - Yun Nah Lee
- Digestive Disease Center and Research Institute, Department of Internal Medicine, SoonChunHyang University School of Medicine, Bucheon, Korea
| | - Jun Ho Myeong
- Digestive Disease Center and Research Institute, Department of Internal Medicine, SoonChunHyang University School of Medicine, Bucheon, Korea
| | - Tae Hoon Lee
- Digestive Disease Center and Research Institute, Department of Internal Medicine, SoonChunHyang University School of Medicine, Cheonan, Korea
| | - Jae Kook Yang
- Digestive Disease Center and Research Institute, Department of Internal Medicine, SoonChunHyang University School of Medicine, Cheonan, Korea
| | - Young Deok Cho
- Digestive Disease Center and Research Institute, Department of Internal Medicine, SoonChunHyang University School of Medicine, Seoul, Korea
| | - Sang-Heum Park
- Digestive Disease Center and Research Institute, Department of Internal Medicine, SoonChunHyang University School of Medicine, Cheonan, Korea
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14
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Vargas A, Dutta P, Carpenter ES, Machicado JD. Endoscopic Ultrasound-Guided Ablation of Premalignant Pancreatic Cysts and Pancreatic Cancer. Diagnostics (Basel) 2024; 14:564. [PMID: 38473035 DOI: 10.3390/diagnostics14050564] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Revised: 02/29/2024] [Accepted: 03/04/2024] [Indexed: 03/14/2024] Open
Abstract
Pancreatic cancer is on the rise and expected to become the second leading cause of cancer-related death by 2030. Up to a one-fifth of pancreatic cancers may arise from mucinous pancreatic cysts, which are frequently present in the general population. Currently, surgical resection is the only curative approach for pancreatic cancer and its cystic precursors. However, only a dismal proportion of patients are eligible for surgery. Therefore, novel treatment approaches to treat pancreatic cancer and precancerous pancreatic cysts are needed. Endoscopic ultrasound (EUS)-guided ablation is an emerging minimally invasive method to treat pancreatic cancer and premalignant pancreatic cysts. Different ablative modalities have been used including alcohol, chemotherapy agents, and radiofrequency ablation. Cumulative data over the past two decades have shown that endoscopic ablation of mucinous pancreatic cysts can lead to cyst resolution in a significant proportion of the treated cysts. Furthermore, novel data are emerging about the ability to endoscopically ablate early and locally advanced pancreatic cancer. In this review, we aim to summarize the available data on the efficacy and safety of the different EUS-ablation modalities for the management of premalignant pancreatic cysts and pancreatic cancer.
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Affiliation(s)
- Alejandra Vargas
- Department of Medicine, Eastern Virginia Medical School, Norfolk, VA 23510, USA
| | - Priyata Dutta
- Department of Medicine, Trinity Health, Ann Arbor, MI 48197, USA
| | - Eileen S Carpenter
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Jorge D Machicado
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI 48109, USA
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15
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Erdem S, Narayanan JS, Worni M, Bolli M, White RR. Local ablative therapies and the effect on antitumor immune responses in pancreatic cancer - A review. Heliyon 2024; 10:e23551. [PMID: 38187292 PMCID: PMC10767140 DOI: 10.1016/j.heliyon.2023.e23551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2023] [Revised: 12/05/2023] [Accepted: 12/06/2023] [Indexed: 01/09/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease, projected to rank as the second most prevalent cause of cancer-related mortality by 2030. Despite significant progress in advances in surgical techniques and chemotherapy protocols, the overall survival (OS) remains to be less than 10 % for all stages combined. In recent years, local ablative techniques have been introduced and utilized as additional therapeutic approaches for locally advanced pancreatic cancer (LAPC), with promising results with respect to local tumor control and OS. In addition to successful cytoreduction, there is emerging evidence that local ablation induces antitumor immune activity that could prevent or even treat distant metastatic tumors. The enhancement of antitumor immune responses could potentially make ablative therapy a therapeutic option for the treatment of metastatic PDAC. In this review, we summarize current ablative techniques used in the management of LAPC and their impact on systemic immune responses.
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Affiliation(s)
- Suna Erdem
- Moores Cancer Center, University of California San Diego, CA, USA
- Clarunis, Department of Visceral Surgery, University Centre for Gastrointestinal and Liver Diseases, St. Clara Hospital and University Hospital Basel, Basel, Switzerland
| | | | - Mathias Worni
- Department of Surgery, Hirslanden Clinic Beau Site, Bern, Switzerland
- Department of Surgery, Duke University Switzerland
- Clarunis, Department of Visceral Surgery, University Centre for Gastrointestinal and Liver Diseases, St. Clara Hospital and University Hospital Basel, Basel, Switzerland
- Medical Center, Duke University, Durham, NC, USA
- Swiss Institute for Translational and Entrepreneurial Medicine, Stiftung Lindenhof, Campus SLB, Bern, Switzerland
| | - Martin Bolli
- Clarunis, Department of Visceral Surgery, University Centre for Gastrointestinal and Liver Diseases, St. Clara Hospital and University Hospital Basel, Basel, Switzerland
| | - Rebekah R. White
- Moores Cancer Center, University of California San Diego, CA, USA
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16
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Digestive Endoscopology Branch of Chinese Medical Association, Digestive Endoscopy Professional Committee, Endoscopic Physicians Branch of Chinese Medical Doctor Association, National Clinical Research Center for Digestive Diseases (Shanghai). Consensus statements on endoscopic radiofrequency ablation for malignant biliary strictures. J Dig Dis 2024; 25:2-13. [PMID: 38126618 DOI: 10.1111/1751-2980.13248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Accepted: 12/19/2023] [Indexed: 12/23/2023]
Abstract
Endoscopy-guided endobiliary radiofrequency ablation has emerged as a novel treatment for malignant biliary strictures in recent years. When combined with biliary stenting and systemic chemotherapy, it can effectively postpone local tumor progression, improve patient's quality of life, and prolong their survival, which is mainly indicated for patients with inoperable extrahepatic cholangiocarcinoma and ampullary cancer. Based on the existing clinical evidence, the Digestive Endoscopology Branch of Chinese Medical Association, the Digestive Endoscopy Professional Committee, Endoscopic Physicians Branch of Chinese Medical Doctor Association, and the National Clinical Research Center for Digestive Diseases (Shanghai) organized relevant experts to discuss the indications, contraindications, technical operation specifications, and prevention and treatment of the complications during endoscopy-guided endobiliary radiofrequency ablation. Consensus statements were established, trying to provide references for standard treatment of malignant biliary tumors in clinical practice.
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17
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Dhar J, Samanta J, Nabi Z, Aggarwal M, Facciorusso A, Conti Bellocchi MC, Crinò SF. Endoscopic ultrasound-guided radiofrequency ablation of pancreatic insulinoma: a state of the art review. Expert Rev Gastroenterol Hepatol 2024; 18:37-53. [PMID: 38383965 DOI: 10.1080/17474124.2024.2321938] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Accepted: 02/19/2024] [Indexed: 02/23/2024]
Abstract
INTRODUCTION Insulinomas are the most common functional pancreatic neuroendocrine tumors (PNETs) that lead to incapacitating hypoglycemia. Guidelines recommend surgical resection as the mainstay of management. However, surgery is fraught with complications, causing significant peri/post-operative morbidity. Since insulinomas are usually benign, solitary, small (<2 cm), and do not need lymphadenectomy, hence, in this regard, endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) is now being increasingly performed, to circumvent these adverse events and impairment of pancreatic function. AREAS COVERED A comprehensive literature search was undertaken across various databases (PubMed/MEDLINE, Embase, Scopus), with no language restriction, for relevant articles (case series, reviews, case reports) pertaining to EUS-RFA for insulinoma and PNETs, till October 2023. In this review, we have explicated the role of EUS-RFA for insulinoma management, detailing thoroughly its mechanism of action, EUS-RFA devices with data on its safety and efficacy, and an algorithmic approach for its management. EXPERT OPINION EUS-RFA is being advocated as a 'mini-invasive' option with the potential to replace surgery as a first-line approach for benign, sporadic, solitary, and small (<2 cm) insulinomas. Under real-time guidance, EUS-RFA has immense precision, is safe, predictable, with acceptable safety profile. Presently, it is being frequently performed for high-risk or inoperable candidates. Current need-of-the-hour is a randomized controlled trial to substantiate its role in the therapeutic algorithm for insulinoma management.
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Affiliation(s)
- Jahnvi Dhar
- Department of Gastroenterology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Jayanta Samanta
- Department of Gastroenterology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Zaheer Nabi
- Department of Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, India
| | - Manik Aggarwal
- Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Antonio Facciorusso
- Department Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Maria Cristina Conti Bellocchi
- Diagnostic and Interventional Endoscopy of the Pancreas, The Pancreas Institute, University Hospital of Verona, Verona, Italy
| | - Stefano Francesco Crinò
- Diagnostic and Interventional Endoscopy of the Pancreas, The Pancreas Institute, University Hospital of Verona, Verona, Italy
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18
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Imran KM, Gannon J, Morrison HA, Tupik JD, Tintera B, Nagai-Singer MA, Ivester H, Madanick JM, Hendricks-Wenger A, Uh K, Luyimbazi DT, Edwards M, Coutermarsh-Ott S, Eden K, Byron C, Clark-Deener S, Lee K, Vlaisavljevich E, Allen IC. Successful In Situ Targeting of Pancreatic Tumors in a Novel Orthotopic Porcine Model Using Histotripsy. ULTRASOUND IN MEDICINE & BIOLOGY 2023; 49:2361-2370. [PMID: 37596154 PMCID: PMC10529075 DOI: 10.1016/j.ultrasmedbio.2023.07.013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 07/26/2023] [Accepted: 07/28/2023] [Indexed: 08/20/2023]
Abstract
OBJECTIVE New therapeutic strategies and paradigms are direly needed to treat pancreatic cancer. The absence of a suitable pre-clinical animal model of pancreatic cancer is a major limitation to biomedical device and therapeutic development. Traditionally, pigs have proven to be ideal models, especially in the context of designing human-sized instruments, perfecting surgical techniques and optimizing clinical procedures for use in humans. However, pig studies have typically focused on healthy tissue assessments and are limited to general safety evaluations because of the inability to effectively model human tumors. METHODS Here, we establish an orthotopic porcine model of human pancreatic cancer using RAG2/IL2RG double-knockout immunocompromised pigs and treat the tumors ex vivo and in vivo with histotripsy. RESULTS Using these animals, we describe the successful engraftment of Panc-1 human pancreatic cancer cell line tumors and characterize their development. To illustrate the utility of these animals for therapeutic development, we determine for the first time, the successful targeting of in situ pancreatic tumors using histotripsy. Treatment with histotripsy resulted in partial ablation in vivo and reduction in collagen content in both in vivo tumor in pig pancreas and ex vivo patient tumor. CONCLUSION This study presents a first step toward establishing histotripsy as a non-invasive treatment method for pancreatic cancer and exposes some of the challenges of ultrasound guidance for histotripsy ablation in the pancreas. Simultaneously, we introduce a highly robust model of pancreatic cancer in a large mammal model that could be used to evaluate a variety biomedical devices and therapeutic strategies.
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Affiliation(s)
- Khan Mohammad Imran
- Graduate Program in Translational Biology, Medicine and Health, Virginia Polytechnic Institute and State University, Roanoke, VA, USA; Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA, USA
| | - Jessica Gannon
- Department of Biomedical Engineering and Mechanics, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA
| | - Holly A Morrison
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA, USA
| | - Juselyn D Tupik
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA, USA
| | - Benjamin Tintera
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA, USA; Virginia Tech Carilion School of Medicine, Roanoke, VA, USA
| | - Margaret A Nagai-Singer
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA, USA
| | - Hannah Ivester
- Graduate Program in Translational Biology, Medicine and Health, Virginia Polytechnic Institute and State University, Roanoke, VA, USA; Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA, USA
| | - Justin Markov Madanick
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA, USA
| | - Alissa Hendricks-Wenger
- Graduate Program in Translational Biology, Medicine and Health, Virginia Polytechnic Institute and State University, Roanoke, VA, USA; Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA, USA; Department of Biomedical Engineering and Mechanics, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA; DeBusk College of Osteopathic Medicine, Lincoln Memorial University, Knoxville, TN, USA
| | - Kyungjun Uh
- Division of Animal Science, College of Agriculture Food and Natural Resources, University of Missouri, Columbia, MO, USA
| | - David T Luyimbazi
- Department of Surgery, Carilion Clinic and Virginia Tech Carilion School of Medicine, Roanoke, VA, USA
| | - Michael Edwards
- Department of Small Animal Clinical Sciences, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA, USA
| | - Sheryl Coutermarsh-Ott
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA, USA
| | - Kristin Eden
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA, USA
| | - Christopher Byron
- Department of Large Animal Clinical Sciences, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA, USA
| | - Sherrie Clark-Deener
- Department of Large Animal Clinical Sciences, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA, USA
| | - Kiho Lee
- Division of Animal Science, College of Agriculture Food and Natural Resources, University of Missouri, Columbia, MO, USA
| | - Eli Vlaisavljevich
- Department of Biomedical Engineering and Mechanics, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA
| | - Irving C Allen
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA, USA.
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Tran LC, Özdemir BC, Berger MD. The Role of Immune Checkpoint Inhibitors in Metastatic Pancreatic Cancer: Current State and Outlook. Pharmaceuticals (Basel) 2023; 16:1411. [PMID: 37895882 PMCID: PMC10609661 DOI: 10.3390/ph16101411] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Revised: 09/22/2023] [Accepted: 09/22/2023] [Indexed: 10/29/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest tumors, characterized by its aggressive tumor biology and poor prognosis. While immune checkpoint inhibitors (ICIs) play a major part in the treatment algorithm of various solid tumors, there is still no evidence of clinical benefit from ICI in patients with metastatic PDAC (mPDAC). This might be due to several reasons, such as the inherent low immunogenicity of pancreatic cancer, the dense stroma-rich tumor microenvironment that precludes an efficient migration of antitumoral effector T cells to the cancer cells, and the increased proportion of immunosuppressive immune cells, such as regulatory T cells (Tregs), cancer-associated fibroblasts (CAFs), and myeloid-derived suppressor cells (MDSCs), facilitating tumor growth and invasion. In this review, we provide an overview of the current state of ICIs in mPDAC, report on the biological rationale to implement ICIs into the treatment strategy of pancreatic cancer, and discuss preclinical studies and clinical trials in this field. Additionally, we shed light on the challenges of implementing ICIs into the treatment strategy of PDAC and discuss potential future directions.
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Affiliation(s)
| | | | - Martin D. Berger
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland
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Schepis T, De Lucia SS, Pellegrino A, del Gaudio A, Maresca R, Coppola G, Chiappetta MF, Gasbarrini A, Franceschi F, Candelli M, Nista EC. State-of-the-Art and Upcoming Innovations in Pancreatic Cancer Care: A Step Forward to Precision Medicine. Cancers (Basel) 2023; 15:3423. [PMID: 37444534 PMCID: PMC10341055 DOI: 10.3390/cancers15133423] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Revised: 06/20/2023] [Accepted: 06/27/2023] [Indexed: 07/15/2023] Open
Abstract
Pancreatic cancer remains a social and medical burden despite the tremendous advances that medicine has made in the last two decades. The incidence of pancreatic cancer is increasing, and it continues to be associated with high mortality and morbidity rates. The difficulty of early diagnosis (the lack of specific symptoms and biomarkers at early stages), the aggressiveness of the disease, and its resistance to systemic therapies are the main factors for the poor prognosis of pancreatic cancer. The only curative treatment for pancreatic cancer is surgery, but the vast majority of patients with pancreatic cancer have advanced disease at the time of diagnosis. Pancreatic surgery is among the most challenging surgical procedures, but recent improvements in surgical techniques, careful patient selection, and the availability of minimally invasive techniques (e.g., robotic surgery) have dramatically reduced the morbidity and mortality associated with pancreatic surgery. Patients who are not candidates for surgery may benefit from locoregional and systemic therapy. In some cases (e.g., patients for whom marginal resection is feasible), systemic therapy may be considered a bridge to surgery to allow downstaging of the cancer; in other cases (e.g., metastatic disease), systemic therapy is considered the standard approach with the goal of prolonging patient survival. The complexity of patients with pancreatic cancer requires a personalized and multidisciplinary approach to choose the best treatment for each clinical situation. The aim of this article is to provide a literature review of the available treatments for the different stages of pancreatic cancer.
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Affiliation(s)
- Tommaso Schepis
- Center for Diagnosis and Treatment of Digestive Diseases, CEMAD, Gastroenterology Department, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy; (T.S.); (S.S.D.L.); (A.P.); (A.d.G.); (R.M.); (G.C.); (A.G.)
- Department of Translational Medicine and Surgery, School of Medicine, Catholic University of the Sacred Heart of Rome, 00168 Rome, Italy
| | - Sara Sofia De Lucia
- Center for Diagnosis and Treatment of Digestive Diseases, CEMAD, Gastroenterology Department, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy; (T.S.); (S.S.D.L.); (A.P.); (A.d.G.); (R.M.); (G.C.); (A.G.)
- Department of Translational Medicine and Surgery, School of Medicine, Catholic University of the Sacred Heart of Rome, 00168 Rome, Italy
| | - Antonio Pellegrino
- Center for Diagnosis and Treatment of Digestive Diseases, CEMAD, Gastroenterology Department, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy; (T.S.); (S.S.D.L.); (A.P.); (A.d.G.); (R.M.); (G.C.); (A.G.)
- Department of Translational Medicine and Surgery, School of Medicine, Catholic University of the Sacred Heart of Rome, 00168 Rome, Italy
| | - Angelo del Gaudio
- Center for Diagnosis and Treatment of Digestive Diseases, CEMAD, Gastroenterology Department, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy; (T.S.); (S.S.D.L.); (A.P.); (A.d.G.); (R.M.); (G.C.); (A.G.)
- Department of Translational Medicine and Surgery, School of Medicine, Catholic University of the Sacred Heart of Rome, 00168 Rome, Italy
| | - Rossella Maresca
- Center for Diagnosis and Treatment of Digestive Diseases, CEMAD, Gastroenterology Department, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy; (T.S.); (S.S.D.L.); (A.P.); (A.d.G.); (R.M.); (G.C.); (A.G.)
- Department of Translational Medicine and Surgery, School of Medicine, Catholic University of the Sacred Heart of Rome, 00168 Rome, Italy
| | - Gaetano Coppola
- Center for Diagnosis and Treatment of Digestive Diseases, CEMAD, Gastroenterology Department, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy; (T.S.); (S.S.D.L.); (A.P.); (A.d.G.); (R.M.); (G.C.); (A.G.)
- Department of Translational Medicine and Surgery, School of Medicine, Catholic University of the Sacred Heart of Rome, 00168 Rome, Italy
| | - Michele Francesco Chiappetta
- Section of Gastroenterology and Hepatology, Promise, Policlinico Universitario Paolo Giaccone, 90127 Palermo, Italy;
- IBD-Unit, Department of Clinical and Experimental Medicine, University of Messina, 98122 Messina, Italy
| | - Antonio Gasbarrini
- Center for Diagnosis and Treatment of Digestive Diseases, CEMAD, Gastroenterology Department, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy; (T.S.); (S.S.D.L.); (A.P.); (A.d.G.); (R.M.); (G.C.); (A.G.)
- Department of Translational Medicine and Surgery, School of Medicine, Catholic University of the Sacred Heart of Rome, 00168 Rome, Italy
| | - Francesco Franceschi
- Department of Emergency Anesthesiological and Reanimation Sciences, Fondazione Universitaria Policlinico Agostino Gemelli di Roma, Catholic University of the Sacred Heart of Rome, 00168 Rome, Italy; (F.F.); (M.C.)
| | - Marcello Candelli
- Department of Emergency Anesthesiological and Reanimation Sciences, Fondazione Universitaria Policlinico Agostino Gemelli di Roma, Catholic University of the Sacred Heart of Rome, 00168 Rome, Italy; (F.F.); (M.C.)
| | - Enrico Celestino Nista
- Center for Diagnosis and Treatment of Digestive Diseases, CEMAD, Gastroenterology Department, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy; (T.S.); (S.S.D.L.); (A.P.); (A.d.G.); (R.M.); (G.C.); (A.G.)
- Department of Translational Medicine and Surgery, School of Medicine, Catholic University of the Sacred Heart of Rome, 00168 Rome, Italy
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21
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Inoue T, Yoneda M. Endoscopic intraductal radiofrequency ablation for extrahepatic cholangiocarcinoma: An update (2023). World J Gastrointest Endosc 2023; 15:440-446. [PMID: 37397976 PMCID: PMC10308276 DOI: 10.4253/wjge.v15.i6.440] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 02/15/2023] [Accepted: 05/12/2023] [Indexed: 06/14/2023] Open
Abstract
Recently, endoscopic intraductal radiofrequency ablation (ID-RFA) has attracted attention as a local treatment method for malignant biliary obstruction (MBO). ID-RFA causes coagulative necrosis of the tumor tissue in the stricture and induces exfoliation. Its effects are expected to extend the patency period of biliary stents and prolong the survival period. Evidence for extrahepatic cholangiocarcinoma (eCCA) is gradually accumulating, and some reports show significant therapeutic effects in eCCA patients without distant metastasis. However, it is still far from an established treatment technique, and many unsolved problems remain. Therefore, when performing ID-RFA in clinical practice, it is necessary to understand and grasp the current evidence well and to operate appropriately for the true benefit of the patients. This paper reviews the current status, issues, and prospects of endoscopic ID-RFA for MBO, especially for eCCA.
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Affiliation(s)
- Tadahisa Inoue
- Department of Gastroenterology, Aichi Medical University, Nagakute 480-1195, Aichi, Japan
| | - Masashi Yoneda
- Department of Gastroenterology, Aichi Medical University, Nagakute 480-1195, Aichi, Japan
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22
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Merchant AA, Goebel AM, Willingham FF. Radiofrequency ablation for the management of pancreatic mass lesions. Curr Opin Gastroenterol 2023:00001574-990000000-00066. [PMID: 37097824 DOI: 10.1097/mog.0000000000000939] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/26/2023]
Abstract
PURPOSE OF REVIEW Patients with pancreatic tumors may have limited treatment options. Pancreatic tumor ablation is a novel and emerging treatment modality which can now be performed using endoscopic ultrasound (EUS) guidance. This modality is well suited to guide energy delivery for radiofrequency ablation (RFA) and microwave ablation. These approaches provide minimally invasive, nonsurgical methods for delivering energy to ablate pancreatic tumors in situ. This review summarizes the current data and safety profile for ablation in managing pancreatic cancer and pancreatic neuroendocrine tumors. RECENT FINDINGS RFA uses thermal energy to induce cell death by coagulative necrosis and protein denaturation. Studies have reported increased overall survival in patients with pancreatic tumors treated with EUS-guided RFA in a multimodality systemic approach and when used in palliative surgeries. Radiofrequency ablation may have corollary benefits in inducing an immune-modulatory effect. Tumor marker carbohydrate antigen 19-9 has been reported to decrease in response to RFA. Microwave ablation is an emerging modality. SUMMARY RFA utilizes focal thermal energy to induce cell death. RFA has been applied through open, laparoscopic, and radiographic modalities. EUS-guided approaches are now allowing RFA and microwave ablation to be performed for pancreatic tumors in situ.
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Affiliation(s)
| | - Anna M Goebel
- Emory University School of Medicine, Emory University
| | - Field F Willingham
- Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, Georgia, USA
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23
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Ivanenko М, Sorochan P, Kuzmenko О, Hromakova IS. Markers of inflammation in invasive treatment of coloractal cancer liver metastases. УКРАЇНСЬКИЙ РАДІОЛОГІЧНИЙ ТА ОНКОЛОГІЧНИЙ ЖУРНАЛ 2023; 31:70-82. [DOI: 10.46879/ukroj.1.2023.70-82] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
Abstract
Background. In 25–30% of patients with colorectal cancer (CRC) who have no visible signs of metastasis at the time of surgery, metastases are detected within 5 years. Among the options for local treatment of metastatic liver lesions in patients with CRC, various resection options and minimally invasive methods, in particular radiofrequency ablation (RFA), occupy a prominent place. The inflammatory response caused by surgery is a factor that can negatively affect the course of tumor disease. The inflammatory responses of the body, as well as markers for their evaluation and prognosis in the treatment of CRC metastases, have not yet been sufficiently studied. Purpose – to study the dynamics of inflammatory markers in the invasive treatment of colorectal cancer liver metastases to select the most informative markers for assessing and predicting the degree of inflammatory response. Materials and methods. Clinical and laboratory examination was carried out in 18 patients with CRC during the treatment of metastases in the liver, adenocarcinoma was determined in all patients during histological examination. The examination was carried out in three stages: the day before RFA or resection, on days 3 and 14 after the intervention. Serum levels of insulin and IL-6 were measured using an enzyme-linked immunosorbent assay, and levels of C-reactive protein and ferritin were determined using an automatic biochemical analyser. Results and discussion. Markers of inflammation in patients with CRC with liver metastases after invasive intervention were identified. A significant increase in the levels of circulating C-reactive protein (CRP), IL-6 and ferritin was detected along with an increase in the insulin resistance index (HOMA-IR) on day 3 after RFA and resection. The increase in IL-6 was 2-fold higher and the HOMA-IR index was 1.5-fold higher after resection compared with RFA. Patients after RFA showed an approach of indicators to baseline values on day 14 of the study, while CRP, ferritin, IL-6 and insulin levels in patients after resection decreased by only 20–30% at the same time same period. This is consistent with other studies. In particular, elevated CRP levels are considered as a risk factor for the appearance and progression of CRC.There is also evidence that in patients with operable CRC, preoperative IL-6 levels affect the risk of recurrence. Strong evidence suggests that ferritin is a key mediator of immune dysregulation through direct immunosuppressive and pro-inflammatory effects. The accumulated data from the literature and our own results suggest the role of CRP, IL-6 and ferritin in postoperative inflammatory states as mediators and biomarkers of the further course of CRС, since their appearance identifies patients with a high risk of mortality, and timely or preventive correction of the inflammatory response improves their survival. Conclusions. The results of the study show that the most informative markers of the level of inflammatory response after RFA or surgical resection are the levels of C-reactive protein, IL-6 and ferritin. Moderate inflammatory reaction is shown in the early stages after RFA and pronounced and longer-lasting reaction after surgical treatment. Prediction, assessment of the degree of inflammatory reaction and the feasibility of anti-inflammatory therapy in the early stages after intervention can be determined by the complex of immunological, haematological and biochemical markers studied by us.
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Inoue T, Yoneda M. Recent Updates on Local Ablative Therapy Combined with Chemotherapy for Extrahepatic Cholangiocarcinoma: Photodynamic Therapy and Radiofrequency Ablation. Curr Oncol 2023; 30:2159-2168. [PMID: 36826127 PMCID: PMC9954800 DOI: 10.3390/curroncol30020166] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 01/25/2023] [Accepted: 02/06/2023] [Indexed: 02/12/2023] Open
Abstract
Although chemotherapy constitutes of the first-line standard therapy for unresectable extrahepatic cholangiocarcinoma, the treatment outcomes are unsatisfactory. In recent years, local ablative therapy, which is delivered to the cholangiocarcinoma lesion via the percutaneous or endoscopic approach, has garnered attention for the treatment of unresectable, extrahepatic cholangiocarcinoma. Local ablative therapy, such as photodynamic therapy and radiofrequency ablation, can achieve local tumor control. A synergistic effect may also be expected when local ablative therapy is combined with chemotherapy. However, it is a long way from being entrenched as an established therapeutic technique, and several unresolved problems persist, including the paucity of evidence comparing photodynamic therapy and radiofrequency ablation. Clinical application of photodynamic therapy and radiofrequency ablation requires sound comprehension and assimilation of the available evidence to truly benefit each individual patient. In this study, we reviewed the current status, issues, and future prospects of photodynamic therapy and radiofrequency ablation for extrahepatic cholangiocarcinoma, with a special focus on their combination with chemotherapy.
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Affiliation(s)
- Tadahisa Inoue
- Department of Gastroenterology, Aichi Medical University, 1-1 Yazakokarimata, Nagakute 480-1195, Japan
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25
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Karaisz FG, Elkelany OO, Davies B, Lozanski G, Krishna SG. A Review on Endoscopic Ultrasound-Guided Radiofrequency Ablation (EUS-RFA) of Pancreatic Lesions. Diagnostics (Basel) 2023; 13:536. [PMID: 36766643 PMCID: PMC9914142 DOI: 10.3390/diagnostics13030536] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 01/27/2023] [Accepted: 01/29/2023] [Indexed: 02/05/2023] Open
Abstract
The morbidity associated with pancreatectomies limits surgical options for high-risk patients with pancreatic neoplasms that warrant resection. Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) offers a minimally invasive and potentially definitive means to treat pancreatic neuroendocrine tumors and precancerous pancreatic cystic lesions. In addition, EUS-RFA may play a role in the treatment and palliation of non-surgical cases of pancreatic adenocarcinoma. The efficacy of RFA appears to be further enhanced by systemic immunomodulatory effects. Here, we review current studies on the developing role of EUS-RFA in these pancreatic pathologies.
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Affiliation(s)
- Fred G. Karaisz
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Osama O. Elkelany
- Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Benjamin Davies
- College of Medicine, The Ohio State University, Columbus, OH 43210, USA
| | - Gerard Lozanski
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus OH 43210, USA
| | - Somashekar G. Krishna
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
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Guo D, Qin L, Sun J, Li K, Zang C, Wang Q, Qiao W, Liu B, Zhao Y, Zhang Y. Dynamic Changes of Cytokine Profiles and Their Correlation With Tumor Recurrence Following Thermal Ablation in Hepatocellular Carcinoma. Technol Cancer Res Treat 2023; 22:15330338231190644. [PMID: 37525880 PMCID: PMC10395187 DOI: 10.1177/15330338231190644] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 06/20/2023] [Accepted: 07/04/2023] [Indexed: 08/02/2023] Open
Abstract
The 5-year recurrence rate of thermal ablation for hepatocellular carcinoma (HCC) is high, and whether this treatment strategy induces systemic immune response remains elusive. This study aimed to investigate the effects of thermal ablation on HCC patients' cytokine profiles and to explore the correlation of cytokine profiles with tumor recurrence after ablation. A total of 22 HCC patients were included in this prospective study. The levels of 27 cytokines in the peripheral blood of HCC patients were measured before ablation (baseline), week 1, and week 4 after ablation using a Bio-Plex Pro Human Cytokine 27-plex Assay kit. Cytokines showed different dynamic changing trends after ablation treatment. It was found that the level of IL-6 was significantly elevated at week 1 and returned to the baseline level at week 4 after ablation. The level of IL-10 was slightly reduced at week 1 and significantly decreased at week 4. The levels of MCP-1, macrophage inflammatory protein-1β (MIP-1β), and TNF-α were similarly reduced at week 1 and increased at week 4. The levels of IL-17, platelet-derived growth factor-BB (PDGF-BB), and regulated upon activation, normal T cell expressed and secreted (RANTES) showed little to no change at week 1 while an observable increase at week 4. Patients with a high IL-10 level (2.99 pg/ml) at baseline and low levels of TNF-α (20.4 pg/ml), PDGF-BB (107.78 pg/ml), and RANTES (2303.94 pg/ml) at week 4 were at risk of tumor recurrence during 1-year follow-up. The results suggested that thermal ablation activated systemic immune responses by changing the levels of cytokines. The results also demonstrated that measurement of IL-10 at baseline, TNF-α, PDGF-BB, and RANTES at week 4 after ablation might predict the risk of tumor recurrence.
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Affiliation(s)
- Dandan Guo
- Interventional Therapy Center for Oncology, Beijing You’an Hospital, Capital Medical University, Beijing, China
| | - Ling Qin
- Research Center for Biomedical Resources, Beijing You’an Hospital, Capital Medical University, Beijing, China
| | - Jianping Sun
- Research Center for Biomedical Resources, Beijing You’an Hospital, Capital Medical University, Beijing, China
| | - Kang Li
- Research Center for Biomedical Resources, Beijing You’an Hospital, Capital Medical University, Beijing, China
| | - Chaoran Zang
- Research Center for Biomedical Resources, Beijing You’an Hospital, Capital Medical University, Beijing, China
| | - Qi Wang
- Research Center for Biomedical Resources, Beijing You’an Hospital, Capital Medical University, Beijing, China
| | - Wenying Qiao
- Research Center for Biomedical Resources, Beijing You’an Hospital, Capital Medical University, Beijing, China
| | - Biyu Liu
- Research Center for Biomedical Resources, Beijing You’an Hospital, Capital Medical University, Beijing, China
| | - Yan Zhao
- Department of Clinical Laboratory, Beijing Chest Hospital, Capital Medical University, Beijing, China
| | - Yonghong Zhang
- Interventional Therapy Center for Oncology, Beijing You’an Hospital, Capital Medical University, Beijing, China
- Research Center for Biomedical Resources, Beijing You’an Hospital, Capital Medical University, Beijing, China
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Lu Y, Zhang Q, Wang J, Zhang L. Characteristics and postoperative dynamic changes in circulating CD4 + helper T lymphocytes in patients with breast cancer. Front Oncol 2023; 13:1118346. [PMID: 36925914 PMCID: PMC10011473 DOI: 10.3389/fonc.2023.1118346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Accepted: 02/17/2023] [Indexed: 03/08/2023] Open
Abstract
Introduction Circulating CD4+ helper T cell (Th) subsets provide potentially important information on disease progression in several cancers. In this study, we explored the characteristics and postoperative dynamic changes in circulating CD4+Th subsets in patients with breast cancer. Methods Circulating CD4+Th subsets, including CD4+ naive T cells (Tn), CD4+ central memory T cells (Tcm), CD4+ effector memory T cells (Tem), CD4+CD57+T, and CD4+PD-1+T, were detected with multiparameter flow cytometry. T-test and Wilcoxon rank-sum test were used to compare differences between groups for normally and non-normally distributed continuous variables, respectively. Postoperative dynamic changes in CD4+Th subsets were assessed using the paired-sample rank-sum test. Results Seventy-five patients with invasive breast cancer and fifty-three patients with benign breast tumors were enrolled. Compared with that in patients with benign tumors, the proportion of CD4+Tn in patients with breast cancer patients decreased, whereas the proportion and absolute number of CD4+CD57+T and CD4+PD-1+T increased. Moreover, the proportion of CD4+PD-1+T was correlated with the clinicopathology of breast cancer. After tumor resection, the proportion and absolute number of CD4+Tcm significantly decreased, while those of CD4+Tem significantly increased, compared with preoperative values. Tumor resection caused significant changes in the proportion and absolute number of CD4+CD57+T and CD4+PD-1+ T, both of which showed significant decreases. Discussion We found significant changes in circulating CD4+Th subsets in patients with breast cancer. Additionally, complete tumor resection can benefit the patient as it balances the patient's immunosuppression and immune stress and improves the immune exhaustion and immunosenescence states.
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Affiliation(s)
- Yan Lu
- Clinical Laboratory, DongYang People's Hospital, Dongyang, Zhejiang, China
| | - Qiaohong Zhang
- Clinical Laboratory, DongYang People's Hospital, Dongyang, Zhejiang, China
| | - Jiang Wang
- Department of Breast Surgery, DongYang People's Hospital, Dongyang, Zhejiang, China
| | - Longyi Zhang
- Clinical Laboratory, DongYang People's Hospital, Dongyang, Zhejiang, China
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Farmer W, Hannon G, Ghosh S, Prina-Mello A. Thermal ablation in pancreatic cancer: A scoping review of clinical studies. Front Oncol 2022; 12:1066990. [PMID: 36524000 PMCID: PMC9745020 DOI: 10.3389/fonc.2022.1066990] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Accepted: 11/11/2022] [Indexed: 11/17/2024] Open
Abstract
Background Pancreatic cancer is a deadly cancer with a 5-year survival rate less than 10%. Only 20% of patients are eligible to receive surgery at diagnosis. Hence, new therapies are needed to improve outcomes for non-surgical candidates. Thermal ablation techniques can offer a non-invasive alternative to surgery. Aim The aim of this review is to map the literature for the use of thermal ablative techniques: Radiofrequency ablation (RFA), High-intensity focused ultrasound (HIFU), Microwave ablation (MWA), and Laser ablation (LA) in the management of patients with PC. Methods A search strategy was applied to PUBMED and EMBASE using keywords concerning pancreatic cancer, radiofrequency ablation, ultrasound ablation, laser ablation, and microwave ablation. The studies that fit this inclusion criteria were summarized in table format and results reviewed for interpretation. Results 72 clinical studies were included. Most of the included studies related to RFA (n=35) and HIFU (n=27). The most common study design was retrospective (n=33). Only 3 randomized control trials (RCT) were included, all of which related to RFA. Safety outcomes were reported in 53 of the 72 studies, and survival outcomes were reported in 39. Statistically significant survival benefits were demonstrated in 11 studies. Conclusion The evidence for the benefit of MWA and LA in PC patients is limited. RFA and HIFU are safe and feasible therapies to be used in PC patients. Further RCTs where thermal techniques are standardized and reported are necessary in the future to elucidate thermal ablation's clinical utility, and before an evidence-based decision on its routine use in PC management can be considered.
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Affiliation(s)
- William Farmer
- Nanomedicine and Molecular Imaging Group, Trinity Translational Medicine Institute, Dublin, Ireland
- Laboratory of Biological Characterization of Advanced Materials (LBCAM), Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
| | - Gary Hannon
- Nanomedicine and Molecular Imaging Group, Trinity Translational Medicine Institute, Dublin, Ireland
- Laboratory of Biological Characterization of Advanced Materials (LBCAM), Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
| | - Shubhrima Ghosh
- Nanomedicine and Molecular Imaging Group, Trinity Translational Medicine Institute, Dublin, Ireland
- Laboratory of Biological Characterization of Advanced Materials (LBCAM), Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
| | - Adriele Prina-Mello
- Nanomedicine and Molecular Imaging Group, Trinity Translational Medicine Institute, Dublin, Ireland
- Laboratory of Biological Characterization of Advanced Materials (LBCAM), Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
- Advanced Materials and Bioengineering Research (AMBER) Centre, Centre for Research on Adaptive Nanostructures and Nanodevices (CRANN) Institute, Trinity College Dublin, Dublin, Ireland
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Ardeshna DR, Woods E, Tsung A, Krishna SG. An update on EUS-guided ablative techniques for pancreatic cystic lesions. Endosc Ultrasound 2022; 11:432-441. [PMID: 35313421 PMCID: PMC9921977 DOI: 10.4103/eus-d-21-00178] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 11/30/2021] [Indexed: 11/04/2022] Open
Abstract
Pancreatic cystic lesions (PCLs) are increasingly being recognized due to improvements and widespread use of cross-sectional imaging. With an estimated prevalence of 15% in general population, incidentally discovered PCLs represent a dilemma in management. While pancreatectomies offer a chance of cure, the morbidity is considerable in patients with high surgical risks. More recently, EUS-guided approaches for cyst ablation are being offered in clinical trials for the management of PCLs. EUS-chemoablation studies have progressed from first investigating safety and efficacy of EUS-guided alcohol lavage to single-agent paclitaxel ablation. Recent studies have shown that alcohol lavage may not be required, and long-term resolution can be achieved by chemoablation alone. EUS-guided lauromacrogol ablation and EUS-guided radiofrequency ablation (RFA) are new techniques that have shown promising results in a few small studies. Overall, the current literature suggests that EUS-guided paclitaxel ablation has better cyst resolution rates compared to other existing minimally invasive techniques including ethanol injection, lauromacrogol ablation, or RFA. This article will review EUS-guided PCL ablation approaches and future directions the field is headed into.
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Affiliation(s)
- Devarshi R. Ardeshna
- Department of Internal Medicine, Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Edward Woods
- College of Medicine, Ohio State University, Columbus, Ohio, USA
| | - Allan Tsung
- Division of Surgical Oncology, Department of Surgery, Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Somashekar G. Krishna
- Division of Gastroenterology, Department of Internal Medicine, Ohio State University Wexner Medical Center, Columbus, Ohio, USA
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Inoue T, Ibusuki M, Kitano R, Sakamoto K, Kimoto S, Kobayashi Y, Ohashi T, Sumida Y, Nakade Y, Ito K, Yoneda M. Endobiliary Radiofrequency Ablation Using a Short-Type Balloon Enteroscope in Patients with Surgically Altered Anatomy. Dig Dis Sci 2022; 67:4181-4187. [PMID: 34410572 DOI: 10.1007/s10620-021-07224-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 08/10/2021] [Indexed: 12/09/2022]
Abstract
BACKGROUND Endoscopic radiofrequency ablation (RFA) is expected to prolong stent patency for malignant biliary obstruction (MBO). However, its feasibility when used in conjunction with a balloon enteroscope (BE) in patients with surgically altered anatomy (SAA) remains unknown. AIMS This study aimed to investigate the feasibility of RFA combined with metal stent insertion under BE guidance for MBO in patients with SAA. METHODS Thirty-seven patients who underwent treatment between October 2016 and January 2021 and met the eligibility criteria were investigated retrospectively. Study outcomes included technical and clinical success, recurrent biliary obstruction (RBO), and other adverse events besides RBO associated with RFA with metal stent placement using BE. RESULTS Technical and clinical success rates were 100% (37/37) each. The rates of early and late adverse events were 8.1% (3/37) and 8.1% (3/37), respectively. RBO occurred in 32.4% (12/37) of the patients, and the median time to RBO was 296 days. The cause of RBO was ingrowth in eight patients, overgrowth in three patients, and indeterminate in one patient. All reinterventions for RBO were successful using the BE approach; all ingrowths, except one, were recanalized using additional RFA without additional stent placement. The frequency of reintervention-related adverse events was 9.1% (1/11). The median time to RBO after reintervention was 166 days. CONCLUSIONS This study demonstrated the technical safety and feasibility as well as good long-term outcomes of endobiliary RFA combined with metal stent placement under BE guidance. This approach may be a useful option for treating MBO in patients with SAA.
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Affiliation(s)
- Tadahisa Inoue
- Department of Gastroenterology, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan.
| | - Mayu Ibusuki
- Department of Gastroenterology, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan
| | - Rena Kitano
- Department of Gastroenterology, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan
| | - Kazumasa Sakamoto
- Department of Gastroenterology, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan
| | - Satoshi Kimoto
- Department of Gastroenterology, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan
| | - Yuji Kobayashi
- Department of Gastroenterology, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan
| | - Tomohiko Ohashi
- Department of Gastroenterology, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan
| | - Yoshio Sumida
- Department of Gastroenterology, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan
| | - Yukiomi Nakade
- Department of Gastroenterology, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan
| | - Kiyoaki Ito
- Department of Gastroenterology, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan
| | - Masashi Yoneda
- Department of Gastroenterology, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan
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Choi JH, Lee SH. Endoscopic ultrasound-guided ablation of pancreatic cystic lesions. INTERNATIONAL JOURNAL OF GASTROINTESTINAL INTERVENTION 2022. [DOI: 10.18528/ijgii220027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Affiliation(s)
- Jin Ho Choi
- Department of Internal Medicine, Liver Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Sang Hyub Lee
- Department of Internal Medicine, Liver Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
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Jarosova J, Macinga P, Krupickova L, Fialova M, Hujova A, Mares J, Urban O, Hajer J, Spicak J, Striz I, Hucl T. Impact of Endoluminal Radiofrequency Ablation on Immunity in Pancreatic Cancer and Cholangiocarcinoma. Biomedicines 2022; 10:biomedicines10061331. [PMID: 35740353 PMCID: PMC9219740 DOI: 10.3390/biomedicines10061331] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 06/01/2022] [Accepted: 06/03/2022] [Indexed: 11/16/2022] Open
Abstract
Radiofrequency ablation (RFA) is a mini-invasive loco-regional ablation technique that is increasingly being used as a palliative treatment for pancreatic cancer and cholangiocarcinoma. Ablation-triggered immune system stimulation has been proposed as a mechanism behind the systemic effects of RFA. The aim of our study was to investigate the immune response to endoluminal biliary RFA. Peripheral blood samples were collected from patients with pancreatic cancer and cholangiocarcinoma randomised to receive endoluminal biliary radiofrequency ablation + stent (19 patients) or stent only (21 patients). We observed an early increase in IL-6 levels and a delayed increase in CXCL1, CXCL5, and CXCL11 levels as well as an increase in CD8+ and NK cells. However, these changes were not specific to RFA treatment. Explicitly in response to RFA, we observed a delayed increase in serum CXCL1 levels and an early decrease in the number of anti-inflammatory CD206+ blood monocytes. Our study provides the first evidence of endoluminal biliary RFA-based regulation of the systemic immune response in patients with pancreatic cancer and cholangiocarcinoma. These changes were characterised by a general inflammatory response. RFA-specific activation of the adaptive immune system was not confirmed.
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Affiliation(s)
- Jana Jarosova
- Department of Gastroenterology and Hepatology, Institute for Clinical and Experimental Medicine, Videnska 1958, 140 21 Prague, Czech Republic; (J.J.); (P.M.); (A.H.); (J.S.)
| | - Peter Macinga
- Department of Gastroenterology and Hepatology, Institute for Clinical and Experimental Medicine, Videnska 1958, 140 21 Prague, Czech Republic; (J.J.); (P.M.); (A.H.); (J.S.)
| | - Lenka Krupickova
- Department of Clinical and Transplant Immunology, Institute for Clinical and Experimental Medicine, Videnska 1958, 140 21 Prague, Czech Republic; (L.K.); (M.F.); (I.S.)
| | - Martina Fialova
- Department of Clinical and Transplant Immunology, Institute for Clinical and Experimental Medicine, Videnska 1958, 140 21 Prague, Czech Republic; (L.K.); (M.F.); (I.S.)
| | - Alzbeta Hujova
- Department of Gastroenterology and Hepatology, Institute for Clinical and Experimental Medicine, Videnska 1958, 140 21 Prague, Czech Republic; (J.J.); (P.M.); (A.H.); (J.S.)
| | - Jan Mares
- Department of Data Analysis, Statistics and Artificial Intelligence, Institute for Clinical and Experimental Medicine, Videnska 1958, 140 21 Prague, Czech Republic;
| | - Ondrej Urban
- Department of Internal Medicine II—Gastroenterology and Hepatology, University Hospital Olomouc and Faculty of Medicine and Dentistry, Palacky University Olomouc, I.P. Pavlova 185/6, 779 00 Olomouc, Czech Republic;
| | - Jan Hajer
- Department of Internal Medicine, 3rd Faculty of Medicine, Charles University, University Hospital Kralovske Vinohrady, Srobarova 1150, 100 34 Prague, Czech Republic;
| | - Julius Spicak
- Department of Gastroenterology and Hepatology, Institute for Clinical and Experimental Medicine, Videnska 1958, 140 21 Prague, Czech Republic; (J.J.); (P.M.); (A.H.); (J.S.)
| | - Ilja Striz
- Department of Clinical and Transplant Immunology, Institute for Clinical and Experimental Medicine, Videnska 1958, 140 21 Prague, Czech Republic; (L.K.); (M.F.); (I.S.)
| | - Tomas Hucl
- Department of Gastroenterology and Hepatology, Institute for Clinical and Experimental Medicine, Videnska 1958, 140 21 Prague, Czech Republic; (J.J.); (P.M.); (A.H.); (J.S.)
- Correspondence: ; Tel.: +420-261-362-600
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Comparison of Intraductal RFA Plus Stent versus Stent-Only Treatment for Unresectable Perihilar Cholangiocarcinoma—A Systematic Review and Meta-Analysis. Cancers (Basel) 2022; 14:cancers14092079. [PMID: 35565209 PMCID: PMC9099890 DOI: 10.3390/cancers14092079] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 04/13/2022] [Accepted: 04/18/2022] [Indexed: 11/17/2022] Open
Abstract
Simple Summary In patients with unresectable perihilar cholangiocarcinoma, adequate biliary drainage is essential. Stent patency remains a challenge in these complex patients, as both plastic and metal stent occlusion may occur, necessitating additional drainage procedures. Radiofrequency ablation (RFA) is a promising local treatment that has already proven its usefulness in other malignancies, such as hepatocellular carcinoma. In this meta-analysis and systematic review, we aimed to compare intraductal RFA with stent placement to stent placement alone in patients with unresectable perihilar cholangiocarcinoma. We found that RFA + stent treatment showed a significantly longer overall survival, in comparison to stent-only treatment. Further research is necessary in order to validate these findings to support the implementation of this promising strategy in clinical practice. Abstract Background: One of the cornerstones of palliative treatment for unresectable perihilar cholangiocarcinoma is biliary stent placement in order to restore biliary drainage. In this review, the potential added value of RFA with stent placement in comparison to stent placement alone in patients with unresectable perihilar cholangiocarcinoma is analyzed. Methods: We performed a comprehensive online search for relevant articles in November 2021 (PROSPERO ID: CRD42021288180). The primary endpoint was difference in overall survival. Secondary endpoints included overall survival, stent patency and complications. Only studies comparing survival after RFA + stent placement with stent placement alone were included in the meta-analysis. Non-comparative studies or comparative studies describing stent patency only were included in the systematic review. Results: A total of nine studies, including 217 patients with pCCA who underwent RFA + stent placement and 294 patients who underwent stent-only treatment, met the inclusion criteria for the primary endpoint analysis. Direct comparison between the two treatment groups showed a significantly longer overall survival for RFA + stent treatment, with a pooled HR of 0.65 [95% CI, 0.50–0.84, I2 = 38%]. When all eligible studies were included, RFA + stent treatment revealed an overall survival of 9.5 months [95% CI, 6.3–12.6], whereas survival for stent-only treatment was 7.0 months [95% CI, 5.7–8.2]. Due to the heterogeneity of the data, no pooled data analysis could be performed on stent patency or complications. Conclusions: RFA + stent placement displays promising potential to prolong survival. However, further research incorporating confounding factors like use of palliative chemotherapy is necessary in order to validate these findings.
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Lambin T, Lafon C, Drainville RA, Pioche M, Prat F. Locoregional therapies and their effects on the tumoral microenvironment of pancreatic ductal adenocarcinoma. World J Gastroenterol 2022; 28:1288-1303. [PMID: 35645539 PMCID: PMC9099187 DOI: 10.3748/wjg.v28.i13.1288] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 02/10/2022] [Accepted: 02/27/2022] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is expected to become the second leading cause of death from cancer by 2030. Despite intensive research in the field of therapeutics, the 5-year overall survival is approximately 8%, with only 20% of patients eligible for surgery at the time of diagnosis. The tumoral microenvironment (TME) of the PDAC is one of the main causes for resistance to antitumoral treatments due to the presence of tumor vasculature, stroma, and a modified immune response. The TME of PDAC is characterized by high stiffness due to fibrosis, with hypo microvascular perfusion, along with an immunosuppressive environment that constitutes a barrier to effective antitumoral treatment. While systemic therapies often produce severe side effects that can alter patients' quality of life, locoregional therapies have gained attention since their action is localized to the pancreas and can thus alleviate some of the barriers to effective antitumoral treatment due to their physical effects. Local hyperthermia using radiofrequency ablation and radiation therapy - most commonly using a local high single dose - are the two main modalities holding promise for clinical efficacy. Recently, irreversible electroporation and focused ultrasound-derived cavitation have gained increasing attention. To date, most of the data are limited to preclinical studies, but ongoing clinical trials may help better define the role of these locoregional therapies in the management of PDAC patients.
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Affiliation(s)
- Thomas Lambin
- LabTAU, INSERM, Centre Léon Bérard, Université Lyon 1, Univ Lyon, Lyon 69003, France
- Department of Gastroenterology, Hospices Civils de Lyon, Edouard Herriot Hospital, Lyon 69008, France
| | - Cyril Lafon
- LabTAU, INSERM, Centre Léon Bérard, Université Lyon 1, Univ Lyon, Lyon 69003, France
| | | | - Mathieu Pioche
- Department of Gastroenterology, Hospices Civils de Lyon, Edouard Herriot Hospital, Lyon 69008, France
| | - Frédéric Prat
- Service d’Endoscopie Digestive, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Clichy 92110, France
- INSERM U1016, Institut Cochin, Université de Paris, Paris 75014, France
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Garnier J, Turrini O, Chretien AS, Olive D. Local Ablative Therapy Associated with Immunotherapy in Locally Advanced Pancreatic Cancer: A Solution to Overcome the Double Trouble?-A Comprehensive Review. J Clin Med 2022; 11:1948. [PMID: 35407555 PMCID: PMC8999652 DOI: 10.3390/jcm11071948] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 03/15/2022] [Accepted: 03/24/2022] [Indexed: 02/04/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains a major killer and is a challenging clinical research issue with abysmal survival due to unsatisfactory therapeutic efficacy. Two major issues thwart the treatment of locally advanced nonresectable pancreatic cancer (LAPC): high micrometastasis rate and surgical inaccessibility. Local ablative therapies induce a systemic antitumor response (i.e., abscopal effect) in addition to local effects. Thus, the incorporation of additional therapies could be key to improving immunotherapy's clinical efficacy. In this systematic review, we explore recent applications of local ablative therapies combined with immunotherapy to overcome immune resistance in PDAC and discuss future perspectives and challenges. Particularly, we describe four chemoradiation studies and nine reports on irreversible electroporation (IRE). Clinically, IRE is the ablative therapy of choice, utilized in all but two clinical trials, and may create a favorable microenvironment for immunotherapy. Various immunotherapies have been used in combination with IRE, such as NK cell- or γδ T cell-based therapy, as well as immune checkpoint inhibitors. The results of the clinical trials presented in this review and the advancement potential of these therapies to phase II/III trials remain unknown. A multiple treatment approach involving chemotherapy, local ablation, and immunotherapy holds promise in overcoming the double trouble of LAPC.
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Affiliation(s)
- Jonathan Garnier
- Departement of Surgical Oncology, Institut Paoli-Calmettes, 232 Boulevard de Sainte Marguerite, 13009 Marseille, France
| | - Olivier Turrini
- Departement of Surgical Oncology, Institut Paoli-Calmettes, 232 Boulevard de Sainte Marguerite, 13009 Marseille, France
- Centre de Recherche en Cancérologie de Marseille, Aix-Marseille University, 58 Boulevard Charles Livon, 13007 Marseille, France
| | - Anne-Sophie Chretien
- Centre de Recherche en Cancérologie de Marseille, Aix-Marseille University, 58 Boulevard Charles Livon, 13007 Marseille, France
- Team Immunity and Cancer, U1068 Inserm, UMR7258 Centre National de la Recherche Scientifique, 13009 Marseille, France
- Departement of Immunomonitoring, Institut Paoli-Calmettes, 232 Boulevard de Sainte Marguerite, 13009 Marseille, France
| | - Daniel Olive
- Centre de Recherche en Cancérologie de Marseille, Aix-Marseille University, 58 Boulevard Charles Livon, 13007 Marseille, France
- Team Immunity and Cancer, U1068 Inserm, UMR7258 Centre National de la Recherche Scientifique, 13009 Marseille, France
- Departement of Immunomonitoring, Institut Paoli-Calmettes, 232 Boulevard de Sainte Marguerite, 13009 Marseille, France
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Inoue T, Naitoh I, Kitano R, Ibusuki M, Kobayashi Y, Sumida Y, Nakade Y, Ito K, Yoneda M. Endobiliary Radiofrequency Ablation Combined with Gemcitabine and Cisplatin in Patients with Unresectable Extrahepatic Cholangiocarcinoma. Curr Oncol 2022; 29:2240-2251. [PMID: 35448156 PMCID: PMC9029596 DOI: 10.3390/curroncol29040182] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 03/16/2022] [Accepted: 03/19/2022] [Indexed: 12/16/2022] Open
Abstract
Background: Endobiliary radiofrequency ablation (RFA) is a promising treatment modality for patients with extrahepatic cholangiocarcinoma (eCCA). However, no study has investigated the combined use of endobiliary RFA and gemcitabine plus cisplatin (GC) chemotherapy. This study aimed to examine the feasibility and efficacy of endobiliary RFA with GC therapy for patients with unresectable eCCA. Methods: The study outcomes included overall survival (OS), progression-free survival (PFS), time to recurrent biliary obstruction (RBO), and adverse events associated with the treatment. These parameters were retrospectively compared between 25 patients who underwent RFA with self-expandable metal stent (SEMS) placement followed by GC therapy (with-RFA group) and a control cohort of 25 patients who underwent SEMS placement alone and GC therapy (without-RFA group). Results: The median time to RBO was significantly longer in the with-RFA group (10.7 versus 5.2 months, p = 0.048). The median OS was significantly higher in patients with locally advanced tumors in the with-RFA group (23.1 versus 16.6 months, p = 0.032), but did not differ significantly in patients with metastasis (11.4 versus 8.5 months, p = 0.180). Similarly, the median PFS was significantly higher in the with-RFA group in patients with locally advanced disease (10.1 versus 7.3 months, p = 0.015), while there was no significant difference in patients with metastasis (5.4 versus 4.4 months, p = 0.529). The rates of various toxicities did not differ significantly between the groups. Conclusions: Endobiliary RFA prolonged the patency period of uncovered SEMS combined with GC therapy in patients with eCCA. Although RFA also yielded survival benefits, its effect was restricted to locally advanced tumors.
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Affiliation(s)
- Tadahisa Inoue
- Department of Gastroenterology, Aichi Medical University, 1-1 Yazakokarimata, Nagakute 480-1195, Japan; (R.K.); (M.I.); (Y.K.); (Y.S.); (Y.N.); (K.I.); (M.Y.)
- Correspondence: ; Tel.: +81-561-62-3311; Fax: +81-561-63-3208
| | - Itaru Naitoh
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan;
| | - Rena Kitano
- Department of Gastroenterology, Aichi Medical University, 1-1 Yazakokarimata, Nagakute 480-1195, Japan; (R.K.); (M.I.); (Y.K.); (Y.S.); (Y.N.); (K.I.); (M.Y.)
| | - Mayu Ibusuki
- Department of Gastroenterology, Aichi Medical University, 1-1 Yazakokarimata, Nagakute 480-1195, Japan; (R.K.); (M.I.); (Y.K.); (Y.S.); (Y.N.); (K.I.); (M.Y.)
| | - Yuji Kobayashi
- Department of Gastroenterology, Aichi Medical University, 1-1 Yazakokarimata, Nagakute 480-1195, Japan; (R.K.); (M.I.); (Y.K.); (Y.S.); (Y.N.); (K.I.); (M.Y.)
| | - Yoshio Sumida
- Department of Gastroenterology, Aichi Medical University, 1-1 Yazakokarimata, Nagakute 480-1195, Japan; (R.K.); (M.I.); (Y.K.); (Y.S.); (Y.N.); (K.I.); (M.Y.)
| | - Yukiomi Nakade
- Department of Gastroenterology, Aichi Medical University, 1-1 Yazakokarimata, Nagakute 480-1195, Japan; (R.K.); (M.I.); (Y.K.); (Y.S.); (Y.N.); (K.I.); (M.Y.)
| | - Kiyoaki Ito
- Department of Gastroenterology, Aichi Medical University, 1-1 Yazakokarimata, Nagakute 480-1195, Japan; (R.K.); (M.I.); (Y.K.); (Y.S.); (Y.N.); (K.I.); (M.Y.)
| | - Masashi Yoneda
- Department of Gastroenterology, Aichi Medical University, 1-1 Yazakokarimata, Nagakute 480-1195, Japan; (R.K.); (M.I.); (Y.K.); (Y.S.); (Y.N.); (K.I.); (M.Y.)
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Inoue T, Yoneda M. Updated evidence on the clinical impact of endoscopic radiofrequency ablation in the treatment of malignant biliary obstruction. Dig Endosc 2022; 34:345-358. [PMID: 34107114 DOI: 10.1111/den.14059] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 05/24/2021] [Accepted: 06/08/2021] [Indexed: 12/15/2022]
Abstract
Endoscopic biliary radiofrequency ablation (RFA) was recently developed as a novel adjunctive procedure and a promising therapeutic option in patients with malignant biliary obstruction (MBO). RFA can achieve local tumor control, resulting in improved biliary stent patency and a potential survival benefit. However, the efficacy of biliary RFA remains controversial, and previous studies have shown conflicting results. At present, extrahepatic cholangiocarcinoma is considered the condition most effectively treated by biliary RFA, but there is limited research even on this point. Further, limitations of RFA associated with the devices used during the procedure are an important subject of discussion. In addition to further well-designed clinical trials, development of innovative devices is warranted to investigate and conclusively establish the usefulness of biliary RFA. In this review we summarize the updated evidence regarding the use of endoscopic biliary RFA for MBO and discuss issues that should be addressed in future studies.
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Affiliation(s)
- Tadahisa Inoue
- Department of Gastroenterology, Aichi Medical University, Aichi, Japan
| | - Masashi Yoneda
- Department of Gastroenterology, Aichi Medical University, Aichi, Japan
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Bratanic A, Bozic D, Mestrovic A, Martinovic D, Kumric M, Ticinovic Kurir T, Bozic J. Role of endoscopic ultrasound in anticancer therapy: Current evidence and future perspectives. World J Gastrointest Oncol 2021; 13:1863-1879. [PMID: 35070030 PMCID: PMC8713319 DOI: 10.4251/wjgo.v13.i12.1863] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 05/17/2021] [Accepted: 08/27/2021] [Indexed: 02/06/2023] Open
Abstract
The digestive system is one of the most common sites of malignancies in humans. Since gastrointestinal tumors represent a massive global health burden both in terms of morbidity and health care expenditures, scientists continuously develop novel diagnostic and therapeutic methods to ameliorate the detrimental effects of this group of diseases. Apart from the well-established role of the endoscopic ultrasound (EUS) in the diagnostic course of gastrointestinal and hepatobiliary malignancies, we have recently become acquainted with a vast array of its therapeutic possibilities. A multitude of previously established, evidence-based methods that might now be guided by the EUS emerged: Radiofrequency ablation, brachytherapy, fine needle injection, celiac plexus neurolysis, and endoscopic submucosal dissection. In this review we endeavored to provide a comprehensive overview of the role of these methods in different malignancies of the digestive system, primarily in the treatment and symptom control in pancreatic cancer, and additionally in the management of hepatic, gastrointestinal tumors, and pancreatic cysts.
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Affiliation(s)
- Andre Bratanic
- Department of Gastroenterology and Hepatology, University Hospital of Split, Split 21000, Croatia
| | - Dorotea Bozic
- Department of Gastroenterology and Hepatology, University Hospital of Split, Split 21000, Croatia
| | - Antonio Mestrovic
- Department of Gastroenterology and Hepatology, University Hospital of Split, Split 21000, Croatia
| | - Dinko Martinovic
- Department of Pathophysiology, University of Split School of Medicine, Split 21000, Croatia
| | - Marko Kumric
- Department of Pathophysiology, University of Split School of Medicine, Split 21000, Croatia
| | - Tina Ticinovic Kurir
- Department of Pathophysiology, University of Split School of Medicine, Split 21000, Croatia
- Department of Endocrinology, University Hospital of Split, Split 21000, Croatia
| | - Josko Bozic
- Department of Pathophysiology, University of Split School of Medicine, Split 21000, Croatia
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Mills BN, Qiu H, Drage MG, Chen C, Mathew JS, Garrett-Larsen J, Ye J, Uccello TP, Murphy JD, Belt BA, Lord EM, Katz AW, Linehan DC, Gerber SA. Modulation of the Human Pancreatic Ductal Adenocarcinoma Immune Microenvironment by Stereotactic Body Radiotherapy. Clin Cancer Res 2021; 28:150-162. [PMID: 34862242 DOI: 10.1158/1078-0432.ccr-21-2495] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 08/23/2021] [Accepted: 10/13/2021] [Indexed: 11/16/2022]
Abstract
PURPOSE Stereotactic body radiotherapy (SBRT) is an emerging treatment modality for pancreatic ductal adenocarcinoma (PDAC), which can effectively prime cytotoxic T cells by inducing immunogenic tumor cell death in preclinical models. SBRT effects on human PDAC have yet to be thoroughly investigated; therefore, this study aimed to characterize immunomodulation in the human PDAC tumor microenvironment following therapy. EXPERIMENTAL DESIGN Tumor samples were obtained from patients with resectable PDAC. Radiotherapy was delivered a median of 7 days prior to surgical resection, and sections were analyzed by multiplex IHC (mIHC), RNA sequencing, and T-cell receptor sequencing (TCR-seq). RESULTS Analysis of SBRT-treated tumor tissue indicated reduced tumor cell density and increased immunogenic cell death relative to untreated controls. Radiotherapy promoted collagen deposition; however, vasculature was unaffected and spatial analyses lacked evidence of T-cell sequestration. Conversely, SBRT resulted in fewer tertiary lymphoid structures and failed to lessen or reprogram abundant immune suppressor populations. Higher percentages of PD-1+ T cells were observed following SBRT, and a subset of tumors displayed more clonal T-cell repertoires. CONCLUSIONS These findings suggest that SBRT augmentation of antitumor immunogenicity may be dampened by an overabundance of refractory immunosuppressive populations, and support the continued development of SBRT/immunotherapy combination for human PDAC.
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Affiliation(s)
- Bradley N Mills
- Department of Surgery, University of Rochester Medical Center, Rochester, New York
| | - Haoming Qiu
- Department of Radiation Oncology, University of Rochester Medical Center, Rochester, New York.,Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York
| | - Michael G Drage
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York
| | - Chunmo Chen
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York
| | - Jocelyn S Mathew
- Department of Surgery, University of Rochester Medical Center, Rochester, New York
| | - Jesse Garrett-Larsen
- Department of Surgery, University of Rochester Medical Center, Rochester, New York
| | - Jian Ye
- Department of Surgery, University of Rochester Medical Center, Rochester, New York
| | - Taylor P Uccello
- Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York
| | - Joseph D Murphy
- Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York
| | - Brian A Belt
- Department of Surgery, University of Rochester Medical Center, Rochester, New York
| | - Edith M Lord
- Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York.,Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York
| | - Alan W Katz
- Department of Radiation Oncology, University of Rochester Medical Center, Rochester, New York.,Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York
| | - David C Linehan
- Department of Surgery, University of Rochester Medical Center, Rochester, New York.,Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York
| | - Scott A Gerber
- Department of Surgery, University of Rochester Medical Center, Rochester, New York. .,Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York.,Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York
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Frigerio I, Paiella S, Barbi E, Bianco R, Boz G, Butturini G, Cantore M, Cardarelli N, Mirko D, Fiorentini G, Giardino A, Lionetto G, Malleo G, Mambrini A, Milella M, Passardi A, Regi P, Salvia R, Scopelliti F, Viviani E, Bassi C, Girelli R. Open radiofrequency ablation as upfront treatment for locally advanced pancreatic cancer: Requiem from a randomized controlled trial. Pancreatology 2021; 21:1342-1348. [PMID: 34215498 DOI: 10.1016/j.pan.2021.06.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 06/04/2021] [Accepted: 06/17/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND Local ablation of pancreatic cancer has been suggested as an option to manage locally advanced pancreatic cancer (LAPC) although no robust evidence has been published to date to support its application. The aim of this study is to compare overall survival (OS) and progression-free survival (PFS) in patients receiving both radiofrequency ablation (RFA) and conventional chemoradiotherapy (CHRT) with patients receiving CHRT only. METHODS This is a multicentre prospective randomized controlled trial (RCT). Patients with LAPC diagnosed by the Pancreas-Ablation-Team-Verona were randomly assigned to open RFA (Group A) or CHRT (Group B). Survival analyses were performed using the Kaplan-Meier method and compared using the log-rank test. Statistical significance was set at p < 0.05. RESULTS One hundred LAPC patients were enrolled from January 2014 to August 2016. 33% of patients in Group A did not receive the designated procedure because of intraoperative findings of liver (18.7%) or peritoneal metastases (43.8%), or technical contraindications (37.5%). We did not observe any statistically significant survival benefit from RFA compared to CHRT, neither in terms of OS (medians of 14.2 months and 18.1 months, respectively, p = 0.639) nor PFS (medians of 8 months and 6 months respectively, p = 0.570). Mortality was nil and RFA-related morbidity was 15.6%. In 13% of subjects, conversion to surgery occurred (2 after RFA and 11 after CHRT). CONCLUSIONS This is the first RCT evaluating the impact of upfront RFA in the multimodal treatment of LAPC. Compared to CHRT, RFA alone did not provide any advantage in terms of OS or PFS. It could be considered as a therapeutic option for LAPC within a multimodal context and after neoadjuvant therapies.
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Affiliation(s)
- Isabella Frigerio
- Pancreatic Surgery Unit, Pederzoli Hospital, Peschiera del Garda, Italy.
| | - Salvatore Paiella
- General and Pancreatic Surgery Unit, of the Pancreas Institute of the Verona University Hospital Trust, Verona, Italy
| | - Emilio Barbi
- Department of Radiology, Pederzoli Hospital, Peschiera del Garda, Italy
| | - Roberto Bianco
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Gianni Boz
- Radiation Oncology Department, Centro di Riferimento Oncologico, 33081, Aviano, Italy
| | | | | | - Nadia Cardarelli
- Department of Oncology, San Bortolo General Hospital, Vicenza, Italy
| | - D'Onofrio Mirko
- Department of Radiology, Pancreas Institute, University of Verona, Verona, Italy
| | | | | | - Gabriella Lionetto
- General and Pancreatic Surgery Unit, of the Pancreas Institute of the Verona University Hospital Trust, Verona, Italy
| | - Giuseppe Malleo
- General and Pancreatic Surgery Unit, of the Pancreas Institute of the Verona University Hospital Trust, Verona, Italy
| | - Andrea Mambrini
- Oncological Department, Azienda USL Toscana Nord Ovest, Oncological Unit of Massa Carrara, Carrara, Italy
| | - Michele Milella
- De of Oncology, University of Verona School of Medicine, Verona University Hospital Trust, Verona, Italy
| | - Alessandro Passardi
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Paolo Regi
- Pancreatic Surgery Unit, Pederzoli Hospital, Peschiera del Garda, Italy
| | - Roberto Salvia
- General and Pancreatic Surgery Unit, of the Pancreas Institute of the Verona University Hospital Trust, Verona, Italy
| | | | - Elena Viviani
- General and Pancreatic Surgery Unit, of the Pancreas Institute of the Verona University Hospital Trust, Verona, Italy
| | - Claudio Bassi
- General and Pancreatic Surgery Unit, of the Pancreas Institute of the Verona University Hospital Trust, Verona, Italy.
| | - Roberto Girelli
- Pancreatic Surgery Unit, Pederzoli Hospital, Peschiera del Garda, Italy
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Bibok A, Kim DW, Malafa M, Kis B. Minimally invasive image-guided therapy of primary and metastatic pancreatic cancer. World J Gastroenterol 2021; 27:4322-4341. [PMID: 34366607 PMCID: PMC8316906 DOI: 10.3748/wjg.v27.i27.4322] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 05/21/2021] [Accepted: 06/23/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is a challenging malignancy with limited treatment options and poor life expectancy. The only curative option is surgical resection, but only 15%-20% of patients are resectable at presentation because more than 50% of patients has distant metastasis at diagnosis and the rest of them has locally advanced pancreatic cancer (LAPC). The standard of care first line treatment for LAPC patients is chemotherapy with or without radiation therapy. Recent developments in minimally invasive ablative techniques may add to the treatment armamentarium of LAPC. There are increasing number of studies evaluating these novel ablative techniques, including radiofrequency ablation, microwave ablation, cryoablation and irreversible electroporation. Most studies which included pancreatic tumor ablation, demonstrated improved overall survival in LAPC patients. However, the exact protocols are yet to set up to which stage of the treatment algorithm ablative techniques can be added and in what kind of treatment combinations. Patients with metastatic pancreatic cancer has dismal prognosis with 5-year survival is only 3%. The most common metastatic site is the liver as 90% of pancreatic cancer patients develop liver metastasis. Chemotherapy is the primary treatment option for patients with metastatic pancreatic cancer. However, when the tumor is not responding to chemotherapy or severe drug toxicity develops, locoregional liver-directed therapies can provide an opportunity to control intrahepatic disease progression and improve survival in selected patients. During the last decade new therapeutic options arose with the advancement of minimally invasive technologies to treat pancreatic cancer patients. These new therapies have been a topic of increasing interest due to the severe prognostic implications of locally advanced and metastatic pancreatic cancer and the low comorbid risk of these procedures. This review summarizes new ablative options for patients with LAPC and percutaneous liver-directed therapies for patients with liver-dominant metastatic disease.
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Affiliation(s)
- Andras Bibok
- Department of Diagnostic Imaging and Interventional Radiology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, United States
- Department of Transplantation & Surgery, Radiology Unit, Semmelweis University, Budapest 1085, Hungary
| | - Dae Won Kim
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, United States
| | - Mokenge Malafa
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, United States
| | - Bela Kis
- Department of Diagnostic Imaging and Interventional Radiology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, United States
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de Jong DM, Cahen DL. Endoscopic radiofrequency ablation to prolong survival for unresectable extrahepatic biliary cancer. Gastrointest Endosc 2021; 94:101-102. [PMID: 33926713 DOI: 10.1016/j.gie.2021.02.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Accepted: 02/13/2021] [Indexed: 12/11/2022]
Affiliation(s)
- David M de Jong
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Djuna L Cahen
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands
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Gao DJ, Yang JF, Ma SR, Wu J, Wang TT, Jin HB, Xia MX, Zhang YC, Shen HZ, Ye X, Zhang XF, Hu B. Endoscopic radiofrequency ablation plus plastic stent placement versus stent placement alone for unresectable extrahepatic biliary cancer: a multicenter randomized controlled trial. Gastrointest Endosc 2021; 94:91-100.e2. [PMID: 33359435 DOI: 10.1016/j.gie.2020.12.016] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 12/09/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS We sought to compare the efficacy and safety between endoscopic radiofrequency ablation (RFA) and stent placement alone in patients with unresectable extrahepatic biliary cancer (EBC). METHODS In this randomized controlled trial, patients with locally advanced or metastatic cholangiocarcinoma (CCA) or ampullary cancer who were unsuitable for surgery were recruited from 3 tertiary centers. Eligible patients were randomly assigned to RFA plus plastic stent placement (RFA group) or plastic stent placement alone (stent placement alone group) in a 1:1 ratio. Both groups underwent 2 scheduled interventions with an interval of approximately 3 months. The primary outcome was overall survival (OS). RESULTS Altogether, 174 participants completed the 2 index endoscopic interventions. No significant differences in baseline characteristics were noted between the 2 groups. The median OS was significantly higher in the RFA group (14.3 vs 9.2 months; hazard ratio, .488; 95% confidence interval, .351-.678; P < .001). A survival benefit was also shown in patients with CCA (13.3 vs 9.2 months; hazard ratio, .546; 95% confidence interval, .386-.771; P < .001). However, no significant between-group differences were found in jaundice control or stent patency duration. The postprocedural Karnofsky performance scores were significantly higher in the RFA group until 9 months (all P < .001). Adverse events were comparable between the 2 groups (27.6% vs 19.5%, P = .211), except for acute cholecystitis, which was more frequently observed in the RFA group (9 vs 0, P = .003). CONCLUSIONS Compared with stent placement alone, additional RFA may improve OS and quality of life of patients with inoperable primary EBC who do not undergo systemic treatments. (Clinical trial registration number: NCT01844245.).
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Affiliation(s)
- Dao-Jian Gao
- Department of Gastroenterology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Yangpu District, Shanghai, China
| | - Jian-Feng Yang
- Department of Gastroenterology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Shu-Ren Ma
- Department of Endoscopy, General Hospital of Shenyang Military Region, Shenyang, Liaoning Province, China
| | - Jun Wu
- Department of Gastroenterology, Third Affiliated Hospital, Second Military Medical University, Jiading District, Shanghai, China
| | - Tian-Tian Wang
- Department of Gastroenterology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Yangpu District, Shanghai, China
| | - Hang-Bin Jin
- Department of Gastroenterology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Ming-Xing Xia
- Department of Gastroenterology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Yangpu District, Shanghai, China
| | - Ying-Chun Zhang
- Department of Endoscopy, General Hospital of Shenyang Military Region, Shenyang, Liaoning Province, China
| | - Hong-Zhang Shen
- Department of Gastroenterology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Xin Ye
- Department of Gastroenterology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Yangpu District, Shanghai, China
| | - Xiao-Feng Zhang
- Department of Gastroenterology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Bing Hu
- Department of Gastroenterology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Yangpu District, Shanghai, China; Department of Gastroenterology, Third Affiliated Hospital, Second Military Medical University, Jiading District, Shanghai, China
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Granata V, Grassi R, Fusco R, Belli A, Palaia R, Carrafiello G, Miele V, Grassi R, Petrillo A, Izzo F. Local ablation of pancreatic tumors: State of the art and future perspectives. World J Gastroenterol 2021; 27:3413-3428. [PMID: 34163121 PMCID: PMC8218359 DOI: 10.3748/wjg.v27.i23.3413] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Revised: 03/28/2021] [Accepted: 05/08/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Currently, the technologies most commonly used to treat locally advanced pancreatic cancer are radiofrequency ablation (RFA), microwave ablation, and irreversible (IRE) or reversible electroporation combined with low doses of chemotherapeutic drugs.
AIM To report an overview and updates on ablative techniques in pancreatic cancer.
METHODS Several electronic databases were searched. The search covered the years from January 2000 to January 2021. Moreover, the reference lists of the found papers were analysed for papers not indexed in the electronic databases. All titles and abstracts were analysed.
RESULTS We found 30 studies (14 studies for RFA, 3 for microwave therapy, 10 for IRE, and 3 for electrochemotherapy), comprising 1047 patients, which were analysed further. Two randomized trials were found for IRE. Percutaneous and laparotomy approaches were performed. In the assessed patients, the median maximal diameter of the lesions was in the range of 2.8 to 4.5 cm. All series included patients unfit for surgical treatment, but Martin et al assessed a subgroup of patients with borderline resectable tumours who underwent resection with margin attenuation with IRE. Most studies administered chemotherapy prior to ablative therapies. However, several studies suggest that the key determinant of improved survival is attributable to ablative treatment alone. Nevertheless, the authors suggested chemotherapy before local therapies for several reasons. This strategy may not only downstage a subgroup of patients to curative-intent surgery but also support to recognize patients with biologically unfavourable tumours who would likely not benefit from ablation treatments. Ablation therapies seem safe based on the 1047 patients assessed in this review. The mortality rate ranged from 1.8% to 2%. However, despite the low mortality, the reported rates of severe post procedural complications ranged from 0%-42%. Most reported complications have been self-limiting and manageable. Median overall survival varied between 6.0 and 33 mo. Regarding the technical success rate, assessed papers reported an estimated rate in the range of 85% to 100%. However, the authors reported early recurrence after treatment. A distinct consideration should be made on whether local treatments induce an immune response in the ablated area. Preclinical and clinical studies have shown that RFA is a promising mechanism for inducing antigen-presenting cell infiltration and enhancing the systemic antitumour T-cell immune response and tumour regression.
CONCLUSION In the management of patients with pancreatic cancer, the possibility of a multimodal approach should be considered, and conceptually, the combination of RFA with immunotherapy represents a novel angle of attack against this tumour.
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Affiliation(s)
- Vincenza Granata
- Department of Radiology, Istituto Nazionale Tumori –IRCCS- Fondazione G. Pascale, Naples 80131, Italy
| | - Roberta Grassi
- Department of Radiology, Università degli Studi della Campania Luigi Vanvitelli, Naples 80127, Italy
| | - Roberta Fusco
- Department of Radiology, Istituto Nazionale Tumori –IRCCS- Fondazione G. Pascale, Naples 80131, Italy
| | - Andrea Belli
- Department of Surgery, Istituto Nazionale Tumori –IRCCS- Fondazione G. Pascale, Naples 80131, Italy
| | - Raffaele Palaia
- Department of Surgery, Istituto Nazionale Tumori –IRCCS- Fondazione G. Pascale, Naples 80131, Italy
| | | | - Vittorio Miele
- Italian Society of Medical and Interventional Radiology SIRM, SIRM Foundation Milan 20122, Italy
- Department of Emergency Radiology, San Camillo Hospital, Firenze 50139, Italy
| | - Roberto Grassi
- Department of Radiology, Università degli Studi della Campania Luigi Vanvitelli, Naples 80127, Italy
- Italian Society of Medical and Interventional Radiology SIRM, SIRM Foundation Milan 20122, Italy
| | - Antonella Petrillo
- Department of Radiology, Istituto Nazionale Tumori –IRCCS- Fondazione G. Pascale, Naples 80131, Italy
| | - Francesco Izzo
- Department of Surgery, Istituto Nazionale Tumori –IRCCS- Fondazione G. Pascale, Naples 80131, Italy
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Timmer FE, Geboers B, Nieuwenhuizen S, Schouten EA, Dijkstra M, de Vries JJ, van den Tol MP, de Gruijl TD, Scheffer HJ, Meijerink MR. Locally Advanced Pancreatic Cancer: Percutaneous Management Using Ablation, Brachytherapy, Intra-arterial Chemotherapy, and Intra-tumoral Immunotherapy. Curr Oncol Rep 2021; 23:68. [PMID: 33864144 PMCID: PMC8052234 DOI: 10.1007/s11912-021-01057-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/11/2021] [Indexed: 02/07/2023]
Abstract
PURPOSE OF REVIEW Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive neoplasms, bearing a terrible prognosis. Stage III tumors, also known as locally advanced pancreatic cancer (LAPC), are unresectable, and current palliative chemotherapy regimens have only modestly improved survival in these patients. At this stage of disease, interventional techniques may be of value and further prolong life. The aim of this review was to explore current literature on locoregional percutaneous management for LAPC. RECENT FINDINGS Locoregional percutaneous interventional techniques such as ablation, brachytherapy, and intra-arterial chemotherapy possess cytoreductive abilities and have the potential to increase survival. In addition, recent research demonstrates the immunomodulatory capacities of these treatments. This immune response may be leveraged by combining the interventional techniques with intra-tumoral immunotherapy, possibly creating a durable anti-tumor effect. This multimodality treatment approach is currently being examined in several ongoing clinical trials. The use of certain interventional techniques appears to improve survival in LAPC patients and may work synergistically when combined with immunotherapy. However, definitive conclusions can only be made when large prospective (randomized controlled) trials confirm these results.
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Affiliation(s)
- Florentine E.F. Timmer
- Department of Radiology and Nuclear Medicine, Amsterdam UMC (location VUmc), De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
| | - Bart Geboers
- Department of Radiology and Nuclear Medicine, Amsterdam UMC (location VUmc), De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
| | - Sanne Nieuwenhuizen
- Department of Radiology and Nuclear Medicine, Amsterdam UMC (location VUmc), De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
| | - Evelien A.C. Schouten
- Department of Radiology and Nuclear Medicine, Amsterdam UMC (location VUmc), De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
| | - Madelon Dijkstra
- Department of Radiology and Nuclear Medicine, Amsterdam UMC (location VUmc), De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
| | - Jan J.J. de Vries
- Department of Radiology and Nuclear Medicine, Amsterdam UMC (location VUmc), De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
| | - M. Petrousjka van den Tol
- Department of Surgical Oncology, Amsterdam UMC (location VUmc), De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
| | - Tanja D. de Gruijl
- Department of Medical Oncology, Amsterdam UMC (location VUmc)-Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
| | - Hester J. Scheffer
- Department of Radiology and Nuclear Medicine, Amsterdam UMC (location VUmc), De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
| | - Martijn R. Meijerink
- Department of Radiology and Nuclear Medicine, Amsterdam UMC (location VUmc), De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
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Brandi ML, Agarwal SK, Perrier ND, Lines KE, Valk GD, Thakker RV. Multiple Endocrine Neoplasia Type 1: Latest Insights. Endocr Rev 2021; 42:133-170. [PMID: 33249439 PMCID: PMC7958143 DOI: 10.1210/endrev/bnaa031] [Citation(s) in RCA: 122] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Indexed: 02/06/2023]
Abstract
Multiple endocrine neoplasia type 1 (MEN1), a rare tumor syndrome that is inherited in an autosomal dominant pattern, is continuing to raise great interest for endocrinology, gastroenterology, surgery, radiology, genetics, and molecular biology specialists. There have been 2 major clinical practice guidance papers published in the past 2 decades, with the most recent published 8 years ago. Since then, several new insights on the basic biology and clinical features of MEN1 have appeared in the literature, and those data are discussed in this review. The genetic and molecular interactions of the MEN1-encoded protein menin with transcription factors and chromatin-modifying proteins in cell signaling pathways mediated by transforming growth factor β/bone morphogenetic protein, a few nuclear receptors, Wnt/β-catenin, and Hedgehog, and preclinical studies in mouse models have facilitated the understanding of the pathogenesis of MEN1-associated tumors and potential pharmacological interventions. The advancements in genetic diagnosis have offered a chance to recognize MEN1-related conditions in germline MEN1 mutation-negative patients. There is rapidly accumulating knowledge about clinical presentation in children, adolescents, and pregnancy that is translatable into the management of these very fragile patients. The discoveries about the genetic and molecular signatures of sporadic neuroendocrine tumors support the development of clinical trials with novel targeted therapies, along with advancements in diagnostic tools and surgical approaches. Finally, quality of life studies in patients affected by MEN1 and related conditions represent an effort necessary to develop a pharmacoeconomic interpretation of the problem. Because advances are being made both broadly and in focused areas, this timely review presents and discusses those studies collectively.
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Affiliation(s)
| | | | - Nancy D Perrier
- The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | | | - Gerlof D Valk
- University Medical Center Utrecht, CX Utrecht, the Netherlands
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Zhu N, Huang B, Zhu L, Wang Y. Potential Mechanisms of Triptolide against Diabetic Cardiomyopathy Based on Network Pharmacology Analysis and Molecular Docking. J Diabetes Res 2021; 2021:9944589. [PMID: 34926700 PMCID: PMC8672107 DOI: 10.1155/2021/9944589] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 08/03/2021] [Accepted: 11/16/2021] [Indexed: 01/14/2023] Open
Abstract
The incidence of heart failure was significantly increased in patients with diabetic cardiomyopathy (DCM). The therapeutic effect of triptolide on DCM has been reported, but the underlying mechanisms remain to be elucidated. This study is aimed at investigating the potential targets of triptolide as a therapeutic strategy for DCM using a network pharmacology approach. Triptolide and its targets were identified by the Traditional Chinese Medicine Systems Pharmacology database. DCM-associated protein targets were identified using the comparative toxicogenomics database and the GeneCards database. The networks of triptolide-target genes and DCM-associated target genes were created by Cytoscape. The common targets and enriched pathways were identified by the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. The gene-gene interaction network was analyzed by the GeneMANIA database. The drug-target-pathway network was constructed by Cytoscape. Six candidate protein targets were identified in both triptolide target network and DCM-associated network: STAT3, VEGFA, FOS, TNF, TP53, and TGFB1. The gene-gene interaction based on the targets of triptolide in DCM revealed the interaction of these targets. Additionally, five key targets that were linked to more than three genes were determined as crucial genes. The GO analysis identified 10 biological processes, 2 cellular components, and 10 molecular functions. The KEGG analysis identified 10 signaling pathways. The docking analysis showed that triptolide fits in the binding pockets of all six candidate targets. In conclusion, the present study explored the potential targets and signaling pathways of triptolide as a treatment for DCM. These results illustrate the mechanism of action of triptolide as an anti-DCM agent and contribute to a better understanding of triptolide as a transcriptional regulator of cytokine mRNA expression.
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Affiliation(s)
- Ning Zhu
- Department of Cardiology, The Third Affiliated Hospital of Shanghai University (Wenzhou People's Hospital), No. 299 Guan Road, Wenzhou, 325000 Zhejiang Province, China
| | - Bingwu Huang
- Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 109 Xueyuan West Road, Wenzhou, 325000 Zhejiang Province, China
| | - Liuyan Zhu
- Department of General Practice, The Third Affiliated Hospital of Shanghai University (Wenzhou People's Hospital), No. 299 Guan Road, Wenzhou, 325000 Zhejiang Province, China
| | - Yi Wang
- Department of Cardiology, The Third Affiliated Hospital of Shanghai University (Wenzhou People's Hospital), No. 299 Guan Road, Wenzhou, 325000 Zhejiang Province, China
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Granata V, Grassi R, Fusco R, Setola SV, Palaia R, Belli A, Miele V, Brunese L, Grassi R, Petrillo A, Izzo F. Assessment of Ablation Therapy in Pancreatic Cancer: The Radiologist's Challenge. Front Oncol 2020; 10:560952. [PMID: 33330028 PMCID: PMC7731725 DOI: 10.3389/fonc.2020.560952] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Accepted: 10/30/2020] [Indexed: 12/12/2022] Open
Abstract
This article provides an overview of imaging assessment of ablated pancreatic cancer. Only studies reporting radiological assessment on pancreatic ablated cancer were retained. We found 16 clinical studies that satisfied the inclusion criteria. Radiofrequency ablation and irreversible electroporation have become established treatment modalities because of their efficacy, low complication rates, and availability. Microwave Ablation (MWA) has several advantages over radiofrequency ablation (RFA), which may make it more attractive to treat pancreatic cancer. Electrochemotherapy (ECT) is a very interesting emerging technique, characterized by low complication rate and safety profile. According to the literature, the assessment of the effectiveness of ablative therapies is difficult by means of the Response Evaluation Criteria in Solid Tumors (RECIST) criteria that are not suitable to evaluate the treatment response considering that are related to technique used, the timing of reassessment, and the imaging procedure being used to evaluate the efficacy. RFA causes various appearances on imaging in the ablated zone, correlating to the different effects, such as interstitial edema, hemorrhage, carbonization, necrosis, and fibrosis. Irreversible electroporation (IRE) causes the creation of pores within the cell membrane causing cell death. Experimental studies showed that Diffusion Weigthed Imaging (DWI) extracted parameters could be used to detect therapy effects. No data about functional assessment post MWA is available in literature. Morphologic data extracted by Computed Tomography (CT) or Magnetic Resonance Imaging (MRI) do not allow to differentiate partial, complete, or incomplete response after ECT conversely to functional parameters, obtained with Position Emission Tomography (PET), MRI, and CT.
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Affiliation(s)
- Vincenza Granata
- Radiology Division, Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale, Naples, Italy
| | - Roberta Grassi
- Radiology Division, Universita’ Degli Studi Della Campania Luigi Vanvitelli, Naples, Italy
| | - Roberta Fusco
- Radiology Division, Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale, Naples, Italy
| | - Sergio Venanzio Setola
- Radiology Division, Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale, Naples, Italy
| | - Raffaele Palaia
- Hepatobiliary Surgical Oncology Division, Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale, Naples, Italy
| | - Andrea Belli
- Hepatobiliary Surgical Oncology Division, Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale, Naples, Italy
| | - Vittorio Miele
- Department of Radiology, Careggi University Hospital, Florence, Italy
| | - Luca Brunese
- Department of Medicine and Health Sciences “V. Tiberio,” University of Molise, Campobasso, Italy
| | - Roberto Grassi
- Radiology Division, Universita’ Degli Studi Della Campania Luigi Vanvitelli, Naples, Italy
| | - Antonella Petrillo
- Radiology Division, Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale, Naples, Italy
| | - Francesco Izzo
- Hepatobiliary Surgical Oncology Division, Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale, Naples, Italy
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Sodergren MH, Mangal N, Wasan H, Sadanandam A, Balachandran VP, Jiao LR, Habib N. Immunological combination treatment holds the key to improving survival in pancreatic cancer. J Cancer Res Clin Oncol 2020; 146:2897-2911. [PMID: 32748119 PMCID: PMC7519893 DOI: 10.1007/s00432-020-03332-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 07/22/2020] [Indexed: 12/18/2022]
Abstract
Advances in surgery, peri-operative care and systemic chemotherapy have not significantly improved the prognosis of pancreatic cancer for several decades. Early clinical trials of immunotherapy have yielded disappointing results proposing other means by which the tumour microenvironment serves to decrease the immune response. Additionally, the emergence of various subtypes of pancreatic cancer has emerged as a factor for treatment responses with immunogenic subtypes carrying a better prognosis. Herein we discuss the reasons for the poor response to checkpoint inhibitors and outline a rationale why combination treatments are likely to be most effective. We review the therapies which could provide optimal synergistic effects to immunotherapy including chemotherapy, agents targeting the stroma, co-stimulatory molecules, vaccinations and methods of immunogenic tumour priming including radiofrequency ablation. Finally, we discuss reasons why peri-operative and in particular neoadjuvant combination treatments are likely to be most effective and should be considered for early clinical trials.
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Affiliation(s)
- M H Sodergren
- Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, DuCane Road, London, W12 0HS, UK.
| | - N Mangal
- Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, DuCane Road, London, W12 0HS, UK
| | - H Wasan
- Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, DuCane Road, London, W12 0HS, UK
| | - A Sadanandam
- Division of Molecular Pathology, Institute for Cancer Research, London, UK
- Centre for Molecular Pathology, Royal Marsden Hospital, London, UK
| | - V P Balachandran
- Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, USA
- Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, USA
- David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, USA
| | - L R Jiao
- Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, DuCane Road, London, W12 0HS, UK
| | - N Habib
- Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, DuCane Road, London, W12 0HS, UK
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50
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Cho JH, Jang SI, Lee DK. Recent developments in endoscopic ultrasound-guided radiofrequency ablation for pancreatic lesions. INTERNATIONAL JOURNAL OF GASTROINTESTINAL INTERVENTION 2020. [DOI: 10.18528/ijgii200030] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Affiliation(s)
- Jae Hee Cho
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Sung Ill Jang
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Dong Ki Lee
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
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